HAL fluorescence cystoscopy improves the detection of bladder CIS significantly, which has consequences for clinical management and may improve the patient prognosis. The procedure is easily implemented as an adjunct to standard cystoscopy and it adds no significant risk of complications.

Purpose: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking. Experimental Design: To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues.Results: Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors. Conclusion: Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.A shift in cellular energy production from aerobic oxidation in mitochondria to anaerobic glycolysis is a fundamental property of cancer cells, also called the Warburg effect (1, 2). Otto Warburg postulated that damage of the aerobic energy metabolism is a primary and irreversible event in tumor formation (2). Recently, this hypothesis has been supported by the demonstration that mutations of single enzymes of the mitochondrial energy metabolism are associated with tumorigenesis (3, 4). Germline mutations in distinct subunits of succinate dehydrogenase predispose to hereditary paragangliomas and pheochromocytomas (4, 5). Germline mutations in the fumarate hydratase gene can either cause leiomyoma, leiomyosarcoma, and renal cell carcinoma (3) or Leydig cell tumor (6). Therefore, succinate dehydrogenase and fumarate hydratase are regarded as mitochondrial tumor suppressors for these types of tumors (5).Mitochondrial DNA (mtDNA), the small genome of the mitochondrion, is essential for aerobic energy metabolism and encodes some of the subunits of respiratory chain complexes I, III, and IV, as well as the F 1 F 0 -ATP synthase. Complex I consists of 46 different subunits, with a molecular mass totaling 980 kDa. Seven of these subunits (ND1 -ND6 and ND4L) are encoded by mtDNA; the other complex I genes are located on nuclear chromosomes.Because of its essential role in energy metabolism, the mitochondrial genome has long been suspected of contributing to metabolic alterations in tumors. Such investigations d...

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To elucidate the relationship between tumor genesis and the mitochondrial energy metabolism in renal neoplasms, we studied three individual enzyme activities of the oxidative phosphorylation, two components of the Krebs cycle and the mitochondrial DNA content of renal carcinomas including 29 conventional, five papillary, two unclassified carcinomas with sarcomatoid features and one collecting duct carcinoma. A significant reduction of all mitochondrial enzyme activities including complex V, as well as of the mitochondrial DNA content was detected in 34 of 37 renal carcinoma tissues as compared with control kidney. Mitochondrial enzyme activities and mitochondrial DNA levels were not statistically different between the conventional, papillary and unclassified sarcomatoid type of renal carcinoma and did not correlate with tumour grade, metastasis, ploidy and proliferative activity as determined by Ki-67 staining. Taken together, our data indicate that a co-ordinated down-regulation of all components necessary for mitochondrial energy metabolism occurs in most renal carcinomas as an early event in carcinoma formation, which does not change with progression of the disease.

The concentration of nucleosomes is elevated in blood of patients with diseases which are associated with enhanced cell death. In order to detect these circulating nucleosomes, we used the Cell Death Detection-ELISA plus (CDDE) from Roche Diagnostics (Mannheim, Germany) (details at http:\\biochem.roche.com). For its application in liquid materials we performed various modifications: we introduced a standard curve with nucleosome-rich material, which enabled direct quantification and improved comparability of the values within (CV intraassay :3.0-4.1%) and between several runs (CV interassay :8.6-13.5%), and tested the analytical specificity of the ELISA.Because of the fast elimination of nucleosomes from circulation and their limited stability, we compared plasma and serum matrix and investigated in detail the pre-analytical handling of serum samples which can considerably influence the test results. Careless venipuncture producing hemolysis, delayed centrifugation and bacterial contamination of the blood samples led to false-positive results; delayed stabilization with EDTA and insufficient storage conditions resulted in false-negative values. At temperatures of -20 °C, serum samples which were treated with 10 mM EDTA were stable for at least 6 months. In order to avoid possible interfering factors, we recommend a schedule for the pre-analytical handling of the samples.As the first stage, the possible clinical application was investigated in the sera of 310 persons. Patients with solid tumors (n=220; mean=361 Arbitrary Units (AU)) had considerably higher values than healthy persons (n=50; mean=30 AU; p=0.0001) and patients with inflammatory diseases (n=40; mean= 296 AU; p=0.096). Within the group of patients with tumors, those in advanced stages (UICC 4) showed significantly higher values than those in early stages (UICC 1-3) (p=0.0004).