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Objective: Earlier investigations have demonstrated that inactivation of the p53 tumor suppressor gene might play a role in the development and progression of bladder cancer. Complex formation with the MDM2 oncogene product is one mechanism inactivating the p53 protein. Therefore, the MDM2 and the p53 protein were investigated to study potential interactions in bladder cancer., Method: 200 archival bladder tissue specimens from 92 patients were studied by immunohistochemistry using monoclonal antibodies DO-1 against p53 and IF2 against MDM2., Results: No staining was observed for p53 or MDM2 in normal urothelium. Alterations of both genes were rare in dysplasia. p53 accumulation was observed in 27-44% of the tumor stages examined. MDM2 overexpression increased from 18% in carcinoma in situ to 49% in T1 tumors, but was present in only 22% of the advanced tumors. Alterations of both genes were more frequent in high-grade lesions. To investigate the prognostic impact of these alterations 61 patients with superficial bladder tumors were followed for at least 2 years (mean 51 months). Multivariate analysis demonstrated that multifocal disease and p53 accumulation were significantly correlated with tumor progression (p = 0.0099 and 0.0135). MDM2 overexpression alone had no prognostic significance. Patients with alterations of both genes had a very high risk of tumor progression (p = 0.0064)., Conclusion: These results demonstrate a positive correlation between p53 accumulation and MDM2 overexpression in the progression of bladder cancer which may have prognostic value.

Long-term intermittent urokinase therapy has been developed for patients with severe coronary artery disease and refractory angina pectoris. This therapeutic approach is predominantly effective at the microcirculatory level based on a combination of rheologic and fibrinolytic effects; furthermore, plaque regression seems to be a possible mechanism. Patients with refractory angina pectoris are characterized by severe coronary artery disease without a therapeutic option for conventional revascularization procedures, only slight impairment of left ventricular systolic function and hyperfibrinogenemia, which results in further enhancement of myocardial ischemia due to microcirculatory impairment of blood flow. In this article data on the anti-ischemic effectiveness as well as first results on the impact of this therapeutic approach on hemodynamics are described. A dose-response study, which compared 3 x 50,000 IU with 3 x 500,000 IU urokinase three times a week over a treatment period of 12 weeks demonstrated subjective as well as objective antiischemic effectiveness. Only patients who were treated with 500,000 IU per injection achieved marked increases in exercise capacity, while some patients in the low-dose group presented even with a deterioration of exercise performance. First hemodynamic studies could not show marked changes of systolic parameters, either at rest or during exercise. But a decrease of pulmonary capillary wedge pressure at rest after treatment with 500,000 IU per injection indicates an improvement of diastolic function as a result of enhanced myocardial perfusion. Echocardiographic measurements of transmitral Doppler flow in 21 patients with end-stage coronary artery disease demonstrated normalization of early and late diastolic filling rates in most cases. These changes were accompanied by a reduction of clinical signs of heart failure. Long-term intermittent urokinase therapy is a valuable approach as it not only improves quality of life during the actual treatment period but by the persistence of therapeutic effects following the cessation of therapy.

Apart from the relevance of disorders of lipid metabolism for the clinical and morphological progression of coronary artery disease, coronary thrombosis has received increasing attention in recent years. It is undoubtedly the decisive factor in the pathogenesis of acute coronary syndromes, which is underlined by the therapeutic success of various antithrombotic interventions. Furthermore coronary thrombosis is regarded to be a key factor for morphological disease progression also in stable coronary syndromes, which eventually may lead to critical limitation of myocardial perfusion. This is caused by the formation of subclinical coronary thrombi, which either undergo endogenous lysis or become morphologically fixed as they are incorporated into the plaque. Besides local factors, systemic disturbances of hemostasis and endogenous thrombolysis are of relevance. The concept of thrombotic progression of coronary thrombosis is supported by data on the reduction of morphological disease progression or antiischemic effectiveness of anti-thrombotic interventions like aspirin, low-molecular weight heparin and low-dose intermittent urokinase therapy. Percutaneous transluminal coronary angioplasty results in deep mechanical injury of the vessel wall, which is accompanied by secondary coronary thrombosis in the majority of the cases, not necessarily leading to abrupt vessel closure. Particularly, dilatation of primary thrombus as it has been described as the substrate of the culprit lesion in unstable coronary syndromes, promotes release of thrombin and activation of platelets, which in turn furthers the proliferative processes in the pathogenesis of restenosis. Even though data on the reduction of the rate of restenosis by the use of platelet aggregation inhibitors like aspirin, ticlopidin and dipyridamole have not consistently supported this concept, the EPIC. Study has shown that even in patients with stable angina pectoris clinical restenosis rate may be reduced by a platelet-IIb/IIIa-antagonist.

The case of a 17-year-old boy is described, who had myocardial infarction during scholastic sports 15 minutes after scrotal trauma. Cardiac catheterization revealed a nonstenosed aberrant left circumflex artery originating from the right (anterior) sinus of Valsalva with retroaortic course, which has to be regarded the infarct vessel according to electrocardiographic, ventriculographic, and scintigraphic findings.

Objectives: This dose-response study was designed to test two low dose regimens of urokinase administered over a prolonged time period in patients with chronic refractory angina pectoris with respect to effects on clinical symptoms and objective variables of myocardial ischemia., Background: Patients with severe and chronic refractory angina pectoris in end-stage coronary artery disease represent an increasing clinical problem. Favorable therapeutic effects on myocardial ischemia have been reported for long-term application of low dose urokinase., Methods: Ninety-eight patients with chronic refractory and end-stage coronary artery disease were randomly assigned to two treatment groups: group A (49 patients) received 50,000 IU and group B (49 patients) 500,000 IU of urokinase as an intravenous bolus infection three times a week over a period of 12 weeks. Variables evaluated were number of weekly anginal events, data from ergometric exercise testing with simultaneous electrocardiographic registration, semiquantitative evaluation of Tc-99m 2-methoxy isobutyl isonitrile (MIBI) scans and rheologic variables., Results: After 12 weeks of treatment, anginal symptoms (events/week) were reduced significantly in group B by 70% compared with 24% in group A (p < 0.001). Fibrinogen decreased by 3% in group A and by 33% in group B (p < 0.001). Plasma viscosity and red blood cell aggregation were reduced by 6.4% (p < 0.001) and 19.9% (p < 0.001), respectively, in group B. Objective variables of myocardial ischemia were improved significantly in group B only. No cumulation of coronary ischemic events was observed in group B., Conclusions: Long-term intermittent urokinase therapy in an applied dose of 3 X 500,000 IU/week represents an effective anti-ischemic and antianginal approach for patients with refractory angina pectoris and end-stage coronary artery disease. Apart from rheologic improvement, antithrombotic properties and plaque regression are likely anti-ischemic mechanisms.