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Olaf Dirsch

Publications and source records attributed to Olaf Dirsch.

At least 19 recordsLinked to original sources
PubMed2006

Administration of granulocyte colony stimulating factor after liver transplantation leads to an increased incidence and severity of ischemic biliary lesions in the rat model.

AIM: Recently it has been reported that granulocyte colony stimulating factor (G-CSF) can induce hypercoagulability in healthy bone marrow donors. It is conceivable that the induction of a prothrombotic state in a recipient of an organ graft with already impaired perfusion might cause further deterioration in the transplanted organ. This study evaluated whether G-CSF treatment worsens liver perfusion following liver transplantation in the rat model. METHODS: A non-arterialized rat liver transplantation model was employed to evaluate the effect of G-CSF treatment on the liver in a syngeneic and allogeneic strain combination. Study outcomes included survival time and liver damage as investigated by liver enzymes and liver histology. Observation times were 1 d, 1 wk and 12 wk. RESULTS: Rats treated with G-CSF had increased incidence and severity of biliary damage following liver transplantation. In these animals, hepatocellular necrosis was accentuated in the centrilobular region. These lesions are indicative of impaired perfusion in G-CSF treated animals. CONCLUSION: G-CSF should be used with caution in recipients of liver transplantation, as treatment might enhance preexisting, undetected perfusion problems and ultimately lead to ischemia induced biliary complications.

Animals↗
PubMed2006

Influence of stem cell mobilization and liver regeneration on hepatic parenchymal chimerism in the rat.

BACKGROUND: Despite the newly discovered plasticity of hematopoietic stem cells, their capacity to "transdifferentiate" into parenchymal cells and the regulation of this process is not yet elucidated. The present study was designed to investigate the effect of stem cell mobilization and liver regeneration on this process using a syngeneic rat female-to-male liver transplantation model. METHODS: Rate and frequency of Y-chromosome containing hepatocytes was determined by fluorescence-in situ hybridization (FISH) using a rat Y-chromosome specific probe. Rats were subjected to full-size or partial liver transplantation with and without stem cell mobilization using granulocyte colony stimulating factor (G-CSF). The effect of stem cell mobilization was confirmed by assessing the white blood count and by evaluating the migration of granulopoietic precursor cells to the liver. RESULTS: Treatment with G-CSF induced a twofold increase of peripheral white blood cells and a strong influx of granulopoietic precursor cells into the liver. Transplantation of a partial liver graft was followed by a 90% recovery of the original liver weight within a week, demonstrating the strong regenerative stimulus. Irrespective of the experimental model, the incidence and rate of Y-chromosome containing hepatocytes never exceeded 0.77%. CONCLUSION: Neither stem cell mobilization nor liver regeneration enhanced the incidence or rate of stem cell derived hepatocytes in a liver graft with unimpaired regenerative potential.

Animals↗
PubMed2006

Low prevalence of transfusion transmitted virus (TTV)-like DNA sequences in cystadenolymphoma and pleomorphic adenoma of the salivary glands.

Titers of transfusion transmitted virus (TTV)-like DNA in saliva samples have been reported 100-1,000 times higher than those of the corresponding sera, suggesting viral transmission by saliva droplets. The present study was conducted to determine whether TTV-like DNA sequence elements play a role in the pathogenesis of cystadenolymphoma or pleomorphic adenoma and if the parotid or the submandibular gland is a major source of TTV persistence. Sixty-two archival salivary gland samples (16 cystadenolymphomas, 13 pleomorphic adenomas, and 33 controls) and 23 corresponding saliva samples were examined using a polymerase chain reaction (PCR) for TTV DNA. All PCR products that displayed DNA bands were sequenced. Leder's stain and immunohistochemistry (anti-CD8, anti-CD20, anti-CD45R0, anti-CD68, and anti-Ki67/MiB1) were applied to detect possible changes associated with findings of TTV-like DNA sequences. Tissue displayed TTV-like DNA sequences in 8.1% (5/62; saliva: 47.8%, 11/23). Tissue that contained TTV-like DNA sequences was histologically indistinguishable from samples lacking such DNA. TTV appears to be only a bystander in cystadenolymphoma, pleomorphic adenoma, and other salivary gland affections. Neither of the glands seems to be a major source of TTV persistence.

Adenolymphoma↗
PubMed2006

Dedicated calibration formulas permit correction of differences between measurements by different IVUS devices as demonstrated in atherosclerotic human coronary arteries in vitro.

Serial intravascular ultrasound (IVUS) measurements of coronary vessel dimensions are major endpoints of studies focusing on pharmacological interventions, efficiency of drug eluting stents, and vascular remodeling. In serial studies measurement variability among different IVUS devices may cause substantial misinterpretation and error. We analyzed 33 human coronary plaques in vitro using two different IVUS systems (mechanical IVUS system with a 40 MHz Atlantis SR catheter; solid-state electronic IVUS system with a 20 MHz Invision catheter) and repeatedly measured the total vessel, lumen, and plaque + media cross-sectional area and plaque burden (plaque + media area divided by total vessel area). Between the "raw" measurements made by the two devices, there was a significant difference for both plaque + media area (2.35+/-1.86 mm(2), P < 0.01) and plaque burden (5.39+/-3.68%, P < 0.05). Measurements were then corrected by use of recently introduced calibration formulas; as a result the differences decreased significantly for all IVUS parameters measured ( P < 0.0001). After correction, the remaining differences between the corrected mechanical and solid-state IVUS measurements similar to differences between repeated measurements with the same IVUS device (i.e., the intraobserver variability). Thus, in serial studies the use of different IVUS devices at index and follow-up procedure may introduce a substantial error as a result of system-related differences. The application of dedicated calibration formulas allows for correction for these differences by decreasing such differences to the level of intraobserver variability.

Aged↗
PubMed2006

Magnetic resonance imaging of experimental atherosclerotic plaque: comparison of two ultrasmall superparamagnetic particles of iron oxide.

PURPOSE: To evaluate a new ultrasmall superparamagnetic particles of iron oxide (USPIO) compound, ferumoxytol, as a marker of macrophage activity in atherosclerotic plaques and to compare it to ferumoxtran-10. MATERIALS AND METHODS: Ten mature heritable hyperlipidemic (WHHL) female Watanabe rabbits served as the animal model for atherosclerosis, four coeval female New Zealand White (NZW) rabbits were the control group. Five WHHL and two NZW received a single intravenous injection (250 micromol/kg) of either ferumoxtran-10 or ferumoxytol and were subjected to daily MR examinations on a 1.5T whole body scanner for the next five days. Development of signal intensity changes and susceptibility effects was assessed. Statistical analysis was based on a nonparametric Wilcoxon-Mann-Whitney-U test by using a P value at the 0.05 significance level. On day 5, the rabbits were sacrificed and the aorta was referred to histopathology, distribution of iron particles in the vessel wall was analyzed. RESULTS: MRI was feasible in all animals. Three days after injection of ferumoxytol the highest luminal signal intensity measurements were observed in the ferumoxytol group; the highest measurements were five days after injection in the ferumoxtran-10 group (P < 0.05). In the WHHL, susceptibility effects presented as homogeneous dark lines parallel to the aortic wall after ferumoxytol and spotted areas void of signal after ferumoxtran-10. None of these findings were observed in the NZW control groups. CONCLUSION: Ferumoxtran-10 and ferumoxytol at a respective dose of 250 mumol/kg appear well suited for atherosclerotic plaque detection with MRI in experimental atherosclerosis. Ferumoxytol warrants further analysis in humans.

Animals↗
PubMed2006

Marginal hepatectomy in the rat: from anatomy to surgery.

OBJECTIVE: Based on the 3-dimensional visualization of vascular supply and drainage, a vessel-oriented resection technique was optimized. The new surgical technique was used to determine the maximal reduction in liver mass enabling a 50% 1-week survival rate. BACKGROUND DATA: Determination of the minimal liver mass is necessary in clinical as well as in experimental liver surgery. In rats, survival seems to depend on the surgical technique applied. Extended hepatectomy with removal of 90% of the liver mass was long regarded as a lethal model. Introduction of a vessel-oriented approach enabled long-term survival in this model. METHODS: The lobar and vascular anatomy of rat livers was visualized by plastination of the whole organ, respectively, by corrosion casts of the portal vein, hepatic artery and liver veins. The three-dimensional models were used to extract the underlying anatomic structure. In 90% partial hepatectomy, the liver parenchyma was clamped close to the base of the respective liver lobes (left lateral, median and right, liver lobe). Piercing sutures were placed through the liver parenchyma, so that the stem of portal vein and the accompanying hepatic artery but also the hepatic vein were included. RESULTS: A 1-week survival rate of 100% was achieved after 90% hepatectomy. Extending the procedure to 95% resection by additional removal of the upper caudate lobe led to a 1-week survival rate of 66%; 97% partial hepatectomy, accomplished by additional resection of the lower caudate lobe only leaving the paracaval parts of the liver behind, resulted in 100% lethality within 4 days. CONCLUSIONS: Using a anatomically based, vessel-oriented, parenchyma-preserving surgical technique in 95% liver resections led to long-term survival. This represents the maximal reduction of liver mass compatible with survival.

Animals↗
PubMed2005

Liver transplantation for hepatocellular carcinoma in cirrhosis: is clinical tumor classification before transplantation realistic?

BACKGROUND: The decision of whether to proceed with transplantation in patients with hepatocellular carcinoma (HCC) in cirrhosis is based on clinical and imaging findings. The purpose of our study was to evaluate the accuracy of the current system. MATERIALS AND METHODS: We evaluated data of 70 patients with HCC who underwent liver transplantation (LTx) at our center. We specifically analyzed the correlation between preoperative imaging studies and postoperative anatomopathologic findings. Tumor-node-metastasis, Milan, and University of California San Francisco (UCSF) classifications were used. Patients were divided in 2 groups: (1) Patients undergoing live-donor LTx (LDLTx, n=35) and (2) patients undergoing cadaveric LTx (CLTx, n=35). RESULTS: Only 10 (14.3%) of the 70 patients considered had tumor diameter that was correctly identified by pretransplant radiologic examinations. Twenty-four (34.2%) patients had correct identification of the number of tumors present. Fifty (71.4%) patients had incorrect measurements of tumor diameter of more than 1 cm. Sensitivity of radiologic imaging was especially poor for tumors between 1 and 2 cm and less than 1 cm (21% and 0%, respectively). Best accuracy of 60% was found for both the Milan and UCSF criteria. No significant difference was found between the two patient groups concerning the accuracy of the various systems/criteria of classification. CONCLUSIONS: Current imaging techniques have a high incidence of false-negative and false-positive results when evaluating HCC in cirrhosis. A critical appraisal of patient characteristics together with great caution when interpreting imaging studies is recommended to determine candidacy for transplantation.

Carcinoma, Hepatocellular↗
PubMed2005

Impact of donor gender on male rat recipients of small-for-size liver grafts.

The aim of this study was to assess the impact of donor gender on small-for-size (SFS) liver transplantation in male recipients using a rat model. Adult female or male Lewis rats were used as donors and male Lewis rats as recipients. Size-matched (SM) and SFS liver grafts from either male or female donors were transplanted into male recipients. Animals receiving SFS grafts were sacrificed at postoperative week 1, week 4, and week 12, respectively (n = 6-8 per group), those receiving SM grafts after 3 months. The cumulative survival rate (SVR) in the female-to-male (F-M) SFS group was significantly lower (62%; 13 of 21) compared with the male-to-male (M-M) group (90%; 18 of 20) (P < 0.05). Spontaneous death occurred in the F-M SFS combination either in the early postoperative period (<3 weeks) in animals with confluent hepatic necrosis or in the late postoperative period (>8 weeks) in animals with biliary obstruction. In contrast, no death was observed in the early posttransplantation period after M-M liver transplantation. The relative graft size in the SM F-M group was significantly higher (graft-to-recipient weight ratio [GRWR] 2.40% +/- 0.8%) than in the SFS M-M group (GRWR 1.35% +/- 0.2%; P < 0.001). Regardless of graft size, the outcome was worse in terms of SVR as well as regarding the incidence and severity of biliary complications in F-M compared with M-M liver transplantation. In conclusion, male recipients of female livers had a less favorable outcome irrespective of graft size. Confluent hepatic necrosis as well as biliary obstruction were perceived as consequence of a severe perfusion problem in F-M liver transplantation, which was possibly related to an enhancement of ischemia-reperfusion (I/R) injury by the lack of estrogen in male recipients of female grafts.

Animals↗
PubMed2005

[Non-compaction cardiomyopathy].

Isolated non-compaction of the ventricular myocardium (INVM), also known as left ventricular hypertrabeculation or spongy myocardium, belongs to the "unclassified" cardiomyopathies according to the World Health Organization. The main characteristic of this entity is a prominent trabeculation of the left ventricle with deep intertrabecular recesses communicating with the ventricular cavity. The pathomechanism of INVM is thought to be an arrest in cardiac myogenesis with persistence of embryonic myocardial morphology. The most frequent clinical manifestations include congestive heart failure, ventricular arrhythmias and systemic thromboembolic events. The therapy of INVM comprises standard medical therapy for heart failure.

Cardiomyopathies↗
PubMed2005

The epidermal growth factor receptor tyrosine kinase inhibitor gefitinib sensitizes colon cancer cells to irinotecan.

Epidermal growth factor receptor (EGFR) overactivity plays a significant role in colon cancer biology and has been associated with poor clinical prognosis. Early clinical trials reported efficacy of receptor-targeted compounds, including modulation of clinical irinotecan resistance. We investigated the effects of the EGFR tyrosine kinase inhibitor gefitinib on cellular determinants of irinotecan resistance in human colon cancer cells. At non-cytotoxic concentrations, gefitinib sensitized colon cancer cells to SN-38, the active metabolite of irinotecan. Gefitinib increased the SN-38-mediated induction of protein-linked DNA single-strand breaks in a dose-dependent manner, with no alteration of topoisomerase (Topo) I protein expression or enzymatic activity. Whereas Topo IIbeta protein expression was not affected by gefitinib, significant time- and concentration-dependent downregulation of Topo IIalpha protein and inhibition of its enzymatic function were observed, corresponding to a G1 phase cell cycle arrest. Gefitinib significantly inhibited EGFR-associated signaling molecules, including phospho-mitogen-activated protein kinase or protein kinase C, which may account for decreases in proliferation or topoisomerase activity, respectively. Although a dose-dependent decrease of the BCRP/MXR/ABCP half-transporter was observed under gefitinib, cellular pharmacokinetics revealed no significant differences in accumulation or retention of the active SN-38 lactone using reverse-phase HPLC analysis. This study delineates mechanisms that may contribute to the synergism observed between irinotecan and EGFR inhibitors.

Antigens, Neoplasm↗
PubMed2005

Preliminary investigation of mitoxantrone coating on stent-grafts to inhibit neointimal proliferation.

PURPOSE: To investigate the inhibition of neointimal proliferation induced by a stent-graft loaded with mitoxantrone. METHODS: Stent-grafts with and without mitoxantrone loading (150 microg per device) were inserted into the carotid artery of 7 and 6 rabbits, respectively. After an observation period of 28 days, the animals were sacrificed, and a detailed morphological and morphometric workup of the stented vessels was performed. RESULTS: Uncoated stent-grafts induced a thick neointima (median diameter 97+/-99 microm), whereas no neointima formed in mitoxantrone-loaded stent-grafts. However, the loaded devices were not fully covered by an endothelial layer. The underlying media was significantly thinner (31.8+/-5.6 versus 48.6+/-3.3 microm, p=0.002) and showed a widespread loss of smooth muscle cells. CONCLUSIONS: Mitoxantrone loading of a stent-graft inhibited the formation of a neointima. However, important regenerative processes were prevented as well, indicating a local overdose. More experiments using lower doses are warranted.

Animals↗
PubMed2005

Assessment of liver tissue after radiofrequency ablation: findings with different imaging procedures.

UNLABELLED: Our goal was to assess the typical appearance of normal liver tissue immediately after radiofrequency ablation (RF-ablation) when imaged with contrast-enhanced ultrasound, CT, MRI, 18F-FDG PET, and PET/CT. METHODS: Nineteen RF-ablation sessions were performed on nontumorous liver tissue of 10 Göttingen Mini Pigs. CT, ultrasound, MRI, 18F-FDG PET, and PET/CT were performed immediately after the intervention. All imaging procedures were evaluated qualitatively for areas of increased contrast enhancement (morphologic imaging) and regions of elevated tracer uptake (functional imaging). Images were assessed quantitatively by determination of ratios (r(p/p)) comparing contrast enhancement/tracer uptake in the periphery of the necrosis with contrast enhancement/tracer uptake of normal liver parenchyma. RESULTS: On morphologic imaging, an increase in contrast enhancement surrounding the ablative necrosis was detected in all lesions. Quantification of this area of increased contrast enhancement revealed ratios of r(p/p) = 1.57 +/- 0.2 for CT and r(p/p) = 1.57 +/- 0.19 for MRI. On PET and PET/CT, homogeneous tracer utilization was found surrounding all lesions. There were no areas of a focal or rim-like increase in glucose metabolism. The ratio r(p/p) was found to be 1.05 +/- 0.08 for functional data. Histologic examination revealed pooling of blood in the sinusoids of the lesion's periphery that was caused by outflow obstruction due to the central necrosis. CONCLUSION: On morphologic imaging, a rim-like increase of contrast enhancement was found immediately after RF-ablation resembling peripheral hyperperfusion. This area of contrast enhancement may hamper detection of residual tumor. On the basis of homogeneous tracer distribution surrounding the area of necrosis, PET and PET/CT may serve for early assessment of patients after RF-ablation.

Animals↗
PubMed2004

Melanotic schwannoma of the neck mimicking a malignant melanoma.

We report a case of a 42-year-old female patient who presented with a 5-month history of a right cervical swelling. A fine-needle aspiration biopsy performed elsewhere led to the diagnosis of malignant melanoma. Clinical examination revealed pigmented skin and mucous-membrane lesions of the pharynx. Diagnostic exstirpation of the cervical tumor resulted in the intraoperative diagnosis of a malignant melanoma. Subsequent pathological examination including ultrastructural analysis allowed the revision of the diagnosis to that of melanotic schwannoma, a rare, pigmented nerve sheath tumor. Further analysis of the tissue obtained from neck dissection revealed additional melanotic schwannomas. With regard to prognostic and therapeutic issues, it is necessary to differentiate these tumors from the more common metastatic malignant melanoma. The preoperative differential diagnosis is very difficult, as light microscopy and immunocytochemistry allow no discrimination in small biopsies. Although the occurrence of multiple schwannomas points to a hereditary syndrome, our patient did not fulfill the criteria of Carney's syndrome or other known syndromes, suggesting a so far unknown genetic background.

Adult↗
PubMed2004

Adoptive transfer of immunity: a new strategy to interfere with severe hepatitis virus reinfection after woodchuck liver transplantation.

BACKGROUND: The effective transfer of humoral immunity to hepatitis B virus was first demonstrated after clinical and experimental bone marrow transplantation. This strategy is now evaluated in the woodchuck transplantation model, in which protection from reinfection can be tested. METHODS: Animals negative for woodchuck hepatitis virus (WHV) (n = 3) were vaccinated using plasmids expressing woodchuck hepatitis virus surface (WHs), woodchuck hepatitis virus core (WHc), and woodchuck interferon-gamma in combination with a protein vaccine (WHs antigen [Ag]) three times before liver donation. Control animals (n= 4) received the liver from non-immunized donors. Chronic WHV carriers served as recipients. The viral load in serum and liver tissue was monitored pretransplant and posttransplant for up to 11 weeks by dot blot, Northern blot, Southern blot, and immunohistochemistry for WHc and WhsAg. RESULTS: Donor vaccination was effective, as indicated by the development of anti-WHc and anti-WHs antibodies. Transplanting the livers of these donors resulted in a reduction of viral load in two of three animals. No viral DNA was detected in repeated serum samples by dot-blot hybridization technique. However, polymerase chain reaction for viral DNA extracted from serum was always positive. WHV replication intermediates and WHV RNA were absent in repeated liver biopsies. Only few hepatocytes stained weakly positive for WHc protein and frequency, and the intensity of WHsAg positive hepatocytes was low. The third animal developed severe reinfection within 3 weeks, similar to the woodchucks in the control group. CONCLUSIONS: Liver transplantation from immunized donors to chronic carriers seems to be a promising strategy to reduce and delay severe reinfection, which may be applicable in clinical liver transplantation.

Animals↗
PubMed2004

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.

Adult↗
PubMed2004

Lack of elevated serum carcinoembryonic antigen and calcitonin in medullary thyroid carcinoma.

OBJECTIVE: Medullary thyroid carcinoma (MTC) originates from C-cells. A wide variety of tumor markers including calcitonin (CT), carcinoembryonic antigen (CEA), and chromogranin A are produced by MTC. Surgery remains the only potentially curative therapy, and early detection of the primary remains the most important prognostic factor for a positive outcome for the patient. The following case concerns a 50-year-old woman with histologically proven MTC, who completely lacked serum elevation of both CT and CEA. METHODS: We performed a total thyroidectomy with lymphadenectomy in the central compartment. Histologic sections were stained for CT, CEA, and chromogranin A. Additionally we examined the patient's blood for mutations in the RET proto-oncogene. RESULTS: Serum CT and CEA were below the detection level in the serum. The tumor showed weak staining for CT, but strong staining for CEA and chromogranin A. Sequencing of the RET-proto-oncogene revealed no mutations. Five years after the operation, the patient remains well and shows no signs of tumor recurrence. CONCLUSIONS: We hereby report of a patient with neither plasma elevation of CT nor CEA. From the clinical standpoint, it is important to determine how this subgroup of MTC should be followed because CT and CEA are of no clinical use.

Calcitonin↗