ABSTRACT
Ischemic damage plays an important role in post-transplant organ failure. Activation of the apoptotic cascade is crucially involved in post-ischemic inflammation resulting in tissue damage and organ dysfunction. Here we investigate the initiation of the apoptotic cascade during normothermic ischemia in human kidneys using a model for normothermic ischemia with kidneys nephrectomized because of renal cell carcinoma. Ex vivo, kidneys were stored at 37 degrees C, and consecutive biopsies were taken from disease-free tissue. Pro- and anti-apoptotic proteins were assessed by Western blotting and immunofluorescence. During normothermic ischemia the pro-apoptotic proteins Bax and activated caspase-9 increased with ischemia time, whereas caspase-8 was not activated. The anti-apoptotic proteins Bcl-2 and cFLIP decreased in time. Data on Bcl-2 and Bax were supported by immunofluorescence for Bcl-2 and activated Bax. However, activation of the central effector caspase-3, essential for execution of the apoptotic process, was not detected. In conclusion, during normothermic ischemia the apoptotic cascade in the human kidney is initiated, but not fulfilled. Our data show that the duration of ischemia significantly correlates with activation of the apoptotic cascade. These findings provide insight in the initiation of apoptotic cell-death during warm ischemia and may be useful in the assessment of ischemic injury.
Subject(s)
Apoptosis , Ischemia , Kidney/pathology , Blotting, Western , CASP8 and FADD-Like Apoptosis Regulating Protein , Carcinoma, Renal Cell/pathology , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolism , Enzyme Activation , Hot Temperature , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/metabolism , Ischemia/metabolism , Kidney Neoplasms/pathology , Microscopy, Fluorescence , Proto-Oncogene Proteins c-bcl-2/metabolism , Time Factors , bcl-2-Associated X ProteinABSTRACT
In view of the excellent results of multimodal therapy for nonseminoma testicular tumours, with chemotherapy and surgery, attempts have been made to reduce the side-effects of treatment in patients with a good prognosis, while maintaining efficacy. It is now generally accepted that surveillance after orchidectomy is suitable in patients with low-risk stage I disease. Nerve-sparing retroperitoneal lymph-node dissection as a primary treatment is a good alternative to primary chemotherapy in low-stage disease, i.e. high-risk stage I and stage IIa-b, enabling chemotherapy to be reduced by at least half, and decreasing the long-term side-effects of chemotherapy, especially cardiovascular, neuro-, nephro- and pulmonary toxicity. However, in patients with advanced disease and a poor prognosis, conventional chemotherapy is more likely to fail, and improving the treatment results by new schedules of chemotherapy (although more toxic) remains the main goal.
Subject(s)
Testicular Neoplasms/therapy , Adolescent , Adult , Antineoplastic Agents/adverse effects , Humans , Male , Neoplasm Recurrence, Local/pathology , Neoplasm Staging/methods , Neoplasm, Residual/pathology , Postoperative Complications/etiology , Prognosis , Testicular Neoplasms/pathologyABSTRACT
PURPOSE: Patients with symptomatic metastatic hormone-resistant prostate cancer (HRPC) survive a median of 10 months and are often regarded as a homogeneous group. Few prognostic factors have been identified so far. We examined whether baseline health-related quality of life (HRQOL) parameters assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were independent prognostic factors of survival and whether they bring extra precision to the predictions achievable with models based on clinical and biochemical factors only. PATIENTS AND METHODS: Data of 391 symptomatic (bone) metastatic HRPC patients from three randomized EORTC trials were used in multivariate Cox proportional hazards models. The significance level was set at alpha =.05. RESULTS: Of the 391 patients, 371 died, most of prostate cancer. Bone scan result, performance status, hemoglobin level, and insomnia and appetite loss as measured by the EORTC QLQ-C30 were independent predictors of survival. This model's area under the receiver operating curve was 0.65 compared with 0.63 without the two HRQOL factors. CONCLUSION: Certain HRQOL sores, at baseline, seem to be predictors for duration of survival in HRPC. However, such measurements do not add to the predictive ability of models based only on clinical and biochemical factors.
