Rapamycin reduces neointima formation during vascular injury.

BACKGROUND: Proliferation and migration of vascular smooth muscle cells (SMCs) mark the key processes in the development of bypass graft disease and during neointima formation in restenosis after angioplasty. Growth factors are potent SMC mitogens as they are involved in SMC proliferation and in extracellular matrix (ECM) synthesis. Based on these premises, we examined the effect of the proliferation inhibitor rapamycin in human SMC culture and in a rabbit vascular injury model. MATERIALS AND METHODS: Injection of rapamycin or its vehicle was performed with an infusion-balloon catheter directly into the vessel wall during vascular injury. The intima/media ratio was determined histologically whereas the protein expression was analysed using the powerful two-dimensional gel electrophoresis (2D page) technique. Inhibition of proliferation after rapamycin application was estimated in a human SMC culture for time and dose dependent effects. RESULTS: Rapamycin treatment resulted in a significant reduction of intima media ratio compared to vehicle treated animals after three weeks (0.65 +/- 0.1 vs. 1.2 +/- 0.2 intima-media-ratio, p < 0.05). 2D electrophoresis analysis proved increased ECM synthesis following angioplasty (i.e., lamin, vimentin) in vehicle treated animals. Local rapamycin administration resulted in profound reduction of ECM synthesis after vascular injury. In in-vitro experiments exposure of cultured human SMCs to rapamycin resulted in a significant and dose-dependent (1 nm-100 nm) reduction of human smooth muscle cell proliferation measured by cell counting. CONCLUSION: These above mentioned results suggest that protein synthesis in addition to reduction of cellular proliferation plays an important role following vascular injury, since application of rapamycin resulted in the reduction of SMC proliferation and ECM-synthesis.

Transfection of E-cadherin cDNA in human lung tumor cells reduces invasive potential of tumors.

Lung cancer is a major health-care problem in industrialized countries. With reference to its therapeutic consequences and major histological variations, it is divided into two subgroups - SCLC (small-cell lung cancer) and NSCLC (non-small-cell lung cancer). As an important factor of cell-cell and cell-substratum interaction, cell adhesion molecules (CAMs) seem to play a key role in tumor-cell migration and invasion that lead to metastases. We investigated human lung tumor cell lines established from histologically documented neoplastic lesions taken in our operating theater. Immunohistological screening showed differences in E-cadherin expression with no clear predominance of SCLC or NSCLC cell lines. Using an invasion model with Matrigel Matrix and a migration assay, we could demonstrate a more aggressive behavior pattern in E-cadherin-negative cell lines. We transfected E-cadherin cDNA into a formerly negative cell line showing strong invasive behavior in the initial tests in order to investigate the role of E-cadherin in this process. In this study, we examined E-cadherin cDNA transfection in human bronchial carcinoma cells. At present, transfection is stable with a follow-up time of one year. We could demonstrate that cell lines were remarkably less invasive after transfection of E-cadherin in the invasion model with Matrigel Matrix. These results indicate that the E-cadherin CAM plays an important role in lung tumor invasion and metastasis. Further studies are in progress to confirm these findings and to describe a possible role of this CAM in tumor therapy.

Expression of the proto-oncogene c-myc in human stenotic aortocoronary bypass grafts.

Proliferation and differentiation of vascular smooth muscle cells (VSMC) are central events in vascular pathobiology and play a major role in the development of stenotic and restenotic lesions. The proto-oncogene c-myc and other early cell cycle-regulating genes have been implicated in the induction of cell proliferation and differentiation under diverse pathophysiological conditions. In the present study we analyzed c-myc mRNA expression by indirect nonradioactive in situ hybridization technique (NISH) in human stenotic venous bypass grafts (n = 32) retrieved during re-do operations of coronary artery disease and compared the results with 28 native veins (vena saphena magna) from the same patients. Stenotic bypass grafts showed enhanced c-myc expression located predominantly in VSMC in the media and neointima (severity score: ++-+++, 32/32 stenotic veins). In native veins we observed only low levels of c-myc mRNA (severity score: +, 28/28 native veins), all signals were restricted to endothelial cells of either the innermost intimal layer or of the vasa vasorum. Our in situ hybridization studies demonstrate enhanced mRNA expression of the proto-oncogene c-myc in stenotic venous bypass grafts. These results suggest that--in analogy to other pathophysiological conditions--c-myc exerts essential regulatory functions in cellular events operative during the initiation and progression of venous bypass graft disease.

German Thoracic Research Scholarship 1996: lung volume reduction for endstage pulmonary emphysema at the Washington University of St. Louis.

The Thoracic Research Scholarship 1996 of the German Society for Thoracic and Cardiovascular Surgery enabled me to visit Barnes Hospital at the Washington University of St. Louis, USA, from May to July 1996. At that center Prof. J. D. Cooper has established lung-volume reduction surgery as a successful surgical treatment for patients with endstage pulmonary emphysema. The operation is performed using left-sided double-lumen intubation. After opening of the chest and pleura and starting single-lung ventilation the less diseased parts of the second lung collapse due to absorption atelectasis whereas the more diseased portion of the lung stays hyperinflated. Linear staplers buttressed with bovine pericardium are used to resect the diseased parts of the lungs. Approximately 20-30% of the total lung volume can be resected by this way on each side. After inspection of the lungs for air leaks and preparation of pleural tents the pleura is closed bilaterally. Postoperative analgesia is performed via epidural catheter and patients are extubated postoperatively as soon as possible, usually in the operating theatre. 150 bilateral lung-volume reduction procedures for patients with severe emphysema were performed between January 1993 and February 1996 in St. Louis. 6 months postoperatively the 1-second forced expiratory volume had increased by up to 51% and residual volume was reduced by 28%. 70% of patients who required continuous oxygen supply prior to the operation no longer required this measure: the PaO2 had increased by an average of 8 mmHg. These data demonstrate that bilateral lung-volume reduction surgery is a suitable treatment for patients with terminal pulmonary emphysema. Most important for the success of this procedure are clear selection and specific perioperative treatment of the patients.

[Surgical aspects of pulmonary thrombendarterectomy]. / Chirurgische Aspekte der pulmonalen Thrombendarteriektomie.

Pulmonary thromboendarterectomy is an accepted operative procedure for treatment of pulmonary hypertension due to chronic embolism. Despite its proven value this procedure has been established at very few centers worldwide. In this paper we report our actual operative concept and operative results. Between 8'89 and 4'96 127 patients were operated with use of extracorporeal circulation, deep hypothermia and circulatory arrest. After analysis of the initial high perioperative mortality (26%, 29/108) our operative and postoperative concept changed since 11'94: 1. central incision of both pulmonary arteries, 2. endarterectomy exclusively during circulatory arrest, 3. prolonged reperfusion to 37 degrees C, 4. pressure controlled ventilation, NO-inhalation, early extubation, and 5. modified vasopressor therapy. Preoperatively 12 of the 19 patients were in NYHA class III and 6 in class IV. Mean pulmonary artery pressure was 52(17) mmHg with a calculated pulmonary resistance of 1013(579) dynes.s.cm-5. Mean circulatory arrest time was 37 min (19-57 min) (bypass time 345 min, (240-430 min)). Perioperatively two patients (11%) died (multiorgan failure; rethrombosis of pulmonary artery/right heart failure), all other patients survived (89%). Perioperative complications included reversible renal failure, delirium and postcardiotomy syndrome (1/2/1). Mean pulmonary resistance was postoperatively significantly reduced (362(124) dynes.s.cm-5) (p < 0.01). Early results of pulmonary thromboendarterectomy can be improved by consequent modifications of the intra- and postoperative concept.

[Thymectomy in myasthenia gravis]. / Die Thymektomie bei Myasthenia gravis.

Myasthenia gravis is a relatively uncommon autoimmune disorder of neuromuscular transmission. Surgical therapy plays an important role in addition to medical treatment. Follow-up results of 52 patients with thymectomy are presented. Between 1984-1996 thymectomy via median sternotomy was performed in 52 patients with myasthenia gravis (female = 28, male = 24). The score described by Ossermann and Genkins was used for classification. According to this classification, we found 12 patients in class II(I), 21 in class IIA, 17 in class IIB and 2 in class III, respectively. A thymoma was found in 19, follicular lymphoid hyperplasia in 24 and an atrophic thymus in 9 cases, respectively. There was no mortality. Severe postoperative complications consisted of bleeding and reoperation in one patient and another patient developed a sternal instability with consecutive operative refixation. Follow-up evaluation after a mean period of 36 months (min. 6 months, max. 130 months) revealed a relief of myasthenic symptoms in 37 patients. Thymectomy is effective in the treatment of myasthenia gravis with a low complication rate.

[Early results of pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension]. / Aktuelle Frühergebnisse nach pulmonaler Thrombendarteriektomie bei chronischer thromboembolischer pulmonaler Hypertonie.

Pulmonary thromboendarterectomy (PTE) is a potentially curative procedure in chronic thromboembolic pulmonary hypertension. From June, 1989, to December, 1994, we performed PTE in 109 consecutive patients. Multiple changes in surgical approach and postoperative management have been implemented since January, 1995. We report the early results of 32 thromboendarterectomies performed from January, 1995, to January, 1997. Thirty-two patients (16 females, 16 males; mean age 55 years) were operated using cardiopulmonary bypass, deep hypothermia and circulatory arrest. Preoperative NYHA functional class was III in 21 and IV in 11 patients. Pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mPAP) were elevated to 967 +/- 238 dynes.s.cm-5 and 51 +/- 11 mm Hg respectively. The perioperative mortality rate was 9.3% (3 of 32). Twenty-nine survivors were weaned from mechanical ventilation and extubated after a mean of 35 hours (12 to 190 hours). PVR was reduced to 301 +/- 151 dynes.s.cm-5 (p < 0.001) and mPAP was reduced to 28 +/- 10 mm Hg (p < 0.001). Pulmonary thromboendarterectomy is an effective surgical procedure for chronic thromboembolic pulmonary hypertension. By means of modifications in surgical approach and postoperative management, early results can be improved and perioperative mortality can be decreased to less than 10%.

Expression of cell adhesion molecules in lung cancer cell lines.

Cell adhesion mechanisms are among the basic aspects in organism development. Adhesion molecules are involved in the building of complex structures and of association of the tissue. They also mediate as substratum adhesion molecules and are involved in the building of the scaffold. The process of tumor growth and metastasis is a complex cascade of events (FIDLER 1989). For many of these steps the tumor cells must be able to change their degree of adherence. Tumor progression and metastatic dissemination are tightly linked with the ability of the tumor cells to interact with other cells and with the extracellular matrix. The first step of metastasis is the active migration of tumor cells into the surrounding tissue.