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Distant metastasis is the most predominant clinical problem in renal cell carcinoma. The first step of metastasis is detachment of tumor cells from the primary tumor and subsequent access to the circulation e.g. to lymph or blood vessels. Conceptually, detachment of tumor cells may be facilitated by loss of molecules that provide adhesion of normal cells, such as the cadherins. It has in fact been demonstrated that loss of E-cadherin is associated with invasion and metastasis in animal models and with an unfavorable prognosis in cancer patients. Four major cadherins have been demonstrated in normal kidney and renal cell carcinoma: N-cadherin, E-cadherin, ksp-cadherin, and cadherin 6. The particular role of each of these cadherins in pathogenesis of renal cell carcinoma is not completely understood at present.

Objective: The purpose of this study was to assess a new quantitative urinary tumor marker for transitional cell carcinoma of the urinary bladder (TCC), human complement factor H-related protein (hCFHrp, BTA TRAK)., Methods: Urine samples of 298 individuals (76 healthy volunteers, 118 patients with benign urologic disorders, 104 patients with histologically proven bladder cancer) were examined for the presence of hCFHrp. Samples of all patients were obtained prior to therapy., Results: In comparison to healthy volunteers, patients with TCC had significantly higher urinary levels of hCFHrp (117.60 vs. 2.05 U/ml; p < 0.001). HCFHrp levels were positively correlated with tumor grade and stage. Patients with invasive TCC had significantly higher levels of hCFHrp than patients with superficial TCC (p = 0.001). Marker levels in superficial bladder cancer at high risk of tumor progression (pT1G3) were significantly higher as compared to low and intermediate grade superficial cancers. Elevated levels of hCFHrp were also found in patients with benign urologic disorders (median: 72.65 vs. 117.60 U/ml in cancer patients). Using a cutoff of 17.1 U/ml, hCFHrp had a sensitivity of 72.1% and, due to a high rate of false-positive determinations in patients with benign urologic disorders, a total specificity of 50.5%., Conclusions: HCFHrp (BTA TRAK) is a sensitive test for detection of bladder cancer and for identification of patients at high risk. Due to a high rate of false-positive results in patients with benign urologic diseases, the test should not be used in an unselected population.

Objectives: An important characteristic of malignant cells is their unlimited replicative potential, their immortality. In conferring this immortality, the enzyme telomerase is believed to play a crucial role. The detection of telomerase activity provides new knowledge regarding the biologic growth behavior of tumors and offers new diagnostic and therapeutic tools., Methods: In the present study the sensitive TRAP assay (telomeric repeat amplification protocol) was used to examine 44 malignant renal tumors and 8 benign tumors of the kidney and 52 specimens of normal renal tissue for telomerase activity., Results: Telomerase activity was detected in 63% of tissue samples obtained from histologically confirmed renal cell carcinomas. In cases of renal cell carcinoma restricted to the kidney, telomerase activity was detected in 58%. In cases in which tumor growth has progressed beyond the limits of the organ, telomerase activity was found in 69%. This stage dependence, however, did not reach statistical significance. No correlation to tumor grading was observed. Telomerase activity was found less frequent in chromophobe renal cell carcinomas. Neither the 8 benign renal tumors (4 oncocytomas and 4 angiomyolipomas) nor the specimens of normal kidney showed any evidence of telomerase activity., Conclusions: The proportion of remarkable slow-growing renal cell carcinomas showing telomerase activity is less than in other malignancies and may correlate with biologic growth behavior. Possible explanations include the presence of an alternative pathway, called ALT (alternative lengthening of telomeres) and an association with the loss or presence of the telomerase suppressor on the short arm of chromosome 3. Prolonged follow-up will be of special interest to determine whether lack of telomerase activity predicts favorable outcome.

Deletions of DNA sequences on chromosome 3p [loss of heterozygosity (LOH)] are characteristic of clear cell renal carcinoma, which accounts for about 80% of all renal malignancies. Comparing tumor DNA to DNA from normal cells, LOH analysis of microsatellite sequences has aided in molecular diagnosis of renal carcinoma. Because clinically useful tumor markers do not exist for this cancer entity, the aim of the present study was to detect chromosome 3p microsatellite alterations (LOH and microsatellite instability) in plasma DNA from patients with clear cell renal carcinoma. Four chromosome 3p microsatellites (D3S1307, D3S1560, D3S1289, and D3S1300) were amplified by fluorescent PCR using DNA isolated from normal blood cells and plasma of 40 patients. Corresponding tumor DNA was available from 21 patients. Analyzing PCR products on an automated DNA sequencer, we found LOH in at least one locus in 25 plasma samples (63%), and 14 plasma samples (35%) exhibited LOH at more than one locus. Microsatellite instability of plasma DNA was detectable in one patient (3%). No significant association of advanced (>T2N0M0) tumor stages with LOH in plasma DNA could be demonstrated. If present, modifications of plasma DNA and tumor DNA were identical. No alterations of plasma DNA were found in healthy controls. Analysis of plasma DNA from patients with clear cell renal carcinoma reveals tumor-specific microsatellite alterations and may therefore have diagnostic potential as a molecular tumor marker.

New, noninvasive methods for the early detection of urothelial carcinomas of the urinary bladder are needed for the diagnosis, follow-up, and screening of patients with bladder cancer. Detection of the enzyme telomerase in urine could offer these new diagnostic possibilities. The standard technique for detecting telomerase activity is the telomeric repeat amplification protocol (TRAP assay). Because of the instability of the ribonucleoprotein telomerase in an aggressive medium, such as urine, investigations conducted to date have yielded nonuniform or even contradictory findings. This study compares the detection of human telomerase RNA (hTR) by reverse transcriptase-PCR (RT-PCR) with detection of telomerase activity by the TRAP assay in the diagnosis of urothelial carcinoma of the urinary bladder. Sedimented cells obtained from urine of 30 patients with urothelial carcinoma, 15 patients with benign urological disorders, 3 patients as part of follow-up for malignant disease, and 20 healthy subjects were examined for the presence of hTR and for telomerase activity (TRAP). In patients with bladder cancer, telomerase activity was detected by the TRAP assay in only 2 of 30 specimens (7%). However, increased levels of hTR were detected by RT-PCR in 25 of the same 30 cases (83%). For patients with benign urological disorders, such as urolithiasis or urinary tract infections, hTR was detected in samples obtained from 4 of 15 patients (27%). Low hTR expression levels were found in 15% of the healthy controls. The detection of hTR by RT-PCR represents a promising new method for detecting malignant cells in urine.

Early diagnosis is still the most important prerequisite for successful cancer treatment and this holds true for bladder cancer. Urine cytology is commonly used as a non-invasive screening procedure for the detection of bladder carcinoma, but this method is labour-intensive and often generates false-negative results. The ribonucleoprotein telomerase appears to be promising new cancer marker, since its activity has been reported to correlate with indefinite growth. The aim of this study was to investigate whether telomerase activity can be detected in bladder cancer and in corresponding bladder washings. For this purpose, a sensitive non-radioactive TRAP (telomeric repeat amplification protocol) detection system was developed. With this technique, telomerase activity was found in 95 per cent of the carcinomas (n = 20), in 70 per cent of the corresponding bladder washings, but in none of the urine samples obtained from patients with bladder carcinoma. No telomerase activity was detectable in normal urothelium or in samples from dysplastic urothelium. The data obtained from bladder washings show that superficial carcinoma cells released into the bladder still harbour telomerase activity. The absence of telomerase activity in voided urine is thus most likely due to degradation or inactivation under these conditions. The high rate of telomerase activity in bladder carcinoma indicates that the activation of telomerase in a common step in the tumourigenesis of bladder cancer.

Multivisceral resectioning is the only curative treatment for progressive carcinomas extending beyond the organ. The results of 25 consecutively operated patients are presented in this prospective observational study. Twelve patients underwent surgery for a primary tumor and 13 for a recurrence. Radical resectioning was achieved in 5 of 12 and in 3 of 13 patients. Restoration of continuity obtained in 11 of 12 and in 7 of 13 patients. Morbidity was 33% and 62%. None of the patients died from complications. An aggressive surgical approach is justifiable on account of the acceptable morbidity and mortality as well as the high rate of preserved continence through modern reconstruction procedures.

Objectives: To date, chemotherapy for advanced urothelial carcinoma has been associated with only moderate therapeutic success and minimal extension of survival. This, coupled with the occurrence of serious side effects and the resulting reduced quality of life, underscores the need for new chemotherapeutic agents. A first study investigating combination therapy with etoposide and ifosfamide reported not only comparable therapeutic effectiveness but, due primarily to the elimination of the cisplatin component, a reduction in nephrotoxic side effects. In the present study, therefore, patients with advanced urothelial carcinoma and minor compromised renal function received combination chemotherapy with etoposide and ifosfamide., Methods: Fourteen patients with advanced urothelial carcinoma underwent chemotherapy with a combination of etoposide and ifosfamide. On days 1-5, patients received 1,500 mg/m2 ifosfamide and 120 mg/m2 etoposide. The next corresponding cycle was started on day 22., Results: A number of serious side effects were observed. These consisted predominantly of high-grade myelosuppression requiring therapy, as well as disturbances in the central nervous system and impairment of renal function. Due to severe side effects, chemotherapy had to be prematurely terminated in 8 of 14 patients (57%). The efficacy of therapy, however, was observed in patients completing the treatment regimen., Conclusions: The new combined chemotherapy with etoposide and ifosfamide shows efficacy in the treatment of advanced urothelial carcinoma. This, however, is overshadowed by the high rate of serious side effects leading to premature interruption of therapy.

Objectives: Topically applied photosensitizers are particularly suited for use in the photodynamic therapy of urinary bladder tumors. The objective of the present study was to investigate the photodynamic effects of sulfonated aluminum chlorophthalocyanine on human bladder carcinoma cells., Methods: The photodynamic efficiency and the morphologic changes induced by sulfonated aluminum chlorophthalocyanine on human bladder carcinoma cells and normal bladder wall cells were investigated in vitro using light microscopy and in order to determine the subcellular target organelles using electron microscopy., Results: Examination of tumor cells with light microscopy after previous photodynamic therapy initially showed distension of the cells and, depending on the duration, a significant blistering of the cell membrane, leading, in some cases, to rupture of the cells. Electron microscopy revealed destruction of the mitochondria. No changes in other cell organelles or structures were observed., Conclusions: Sulfonated aluminum chlorophthalocyanine exhibits good photodynamic activity in bladder tumor cells with relative tumor selectivity. The primary cellular target of photodynamic therapy seems to be the mitochondria.

Global exchange of information is one of the major sources of scientific progress in medicine. Electronic media have recently supplemented the standard methods of scientific communication such as congresses, books and journals. Currently, 30 million computers are part of the world-wide, exponentially growing network, the ""information superhighway''. Numerous resources offered by the network are becoming increasingly useful in clinical medicine. In Germany, three major networks are currently available: T-Online/Datex-J, Compuserve and Internet. The majority of information relevant to urologists can be found in the Internet. This information includes medical journals that can either partly or completely be read online, online library catalogs, scientific images (pathology and radiology), and databases on urologic oncology and basic research in urology. Even outside academic institutions access to the "information superhighway" is easily available. Currently, the "information superhighway" constitutes a new source of database-type information; in the near future, medical education, clinical consultation and worldwide cooperation in clinical studies will be new fields of scientific communication employing worldwide computer networks.

Computer equipment in Departments of Urology in Germany was evaluated by a nation-wide questionnaire. One hundred and fifty-three questionnaires were returned with detailed information on computer hardware, software and applications in Urology. Most departments were equipped with at least one computer. Computer equipment varied considerably among the participants including both stand alone personal computers (PCs) and local area networks (LANs) with several PCs connected by cable. Typically, PCs were IBM-compatible and ran the MS-DOS operating system Word processing and related applications were the most frequently mentioned computer tasks in urology. In some departments computers are also used in research for production of databases and graphics and for statistical applications. When computers were used for documentation of therapy and/or medical records, software was often custom-made according to the department's specific needs. In the future, more computers will be needed in departments of urology, because medical records will have to meet higher standards of documentation.

Advanced renal cell carcinoma (RCC) is almost completely resistant to conventional therapeutic approaches such as chemotherapy or radiotherapy. There is growing evidence that few patients may be cured from metastatic RCC by immunotherapy. Unlike 20 years ago, current immunotherapeutic regimens are set up with pure drugs, such as recombinant cytokines. Immunotherapy interferes with a complicated network of cellular immune effectors, e.g., T-lymphocytes, macrophages and natural killer cells. The activity of immune effectors cells is regulated and fine-tuned by a variety of cytokines, e.g., interleukins and interferons which are produced predominantly by the immune effector cells themselves. It is reasonable to expect that in the near future more patients will benefit from immunotherapy for RCC as the knowledge on regulation of the immune response to tumors is rapidly increasing.

In 35 consecutive patients who underwent esophagectomy for malignancy the nutritional status was evaluated. 15 patients were estimated to be malnourished and were therefore treated by total parental nutrition (TPN) for 7 days. In the control group (n = 20, no TPN) the nutritional status was normal. TPN corrected abnormal serum parameters with short half-life time. Therefore the nutritional status of both groups was equal at time of operation. The postoperative clinical outcome of both groups was as follows: In TPN-treated patients postoperative hospital stay for 26 days was shorter compared to 32 days in controls, no patients died (vs n = 4), no patient developed sepsis (vs n = 4), no patient developed acute renal failure (vs n = 3). These differences did not reach levels of significance due to the small patient groups. In conclusion our study shows that patients with esophageal cancer and regarded as well nourished seemed to suffer from nutritional deficits. Assessment of the nutritional status by commonly used nutritional parameters does not reveal these deficits.

Various murine tumor cell lines with different metastatic capacities were tested in vitro for oncogene expression, especially of the p21-Ha-ras protein. Small differences were seen in the expression of several distinct oncogenes in the case of a high metastatic lymphoma variant (ESb) and its low metastatic parental line (Eb). In one instance we observed a 30-fold Ha-ras gene amplification in a metastasis-derived cell line from a spontaneous mouse mammary carcinoma. In spite of this amplification we did not find an increased p21 expression in these cells.

The purpose of these studies was to examine the antiproliferative properties of 16 recombinant human IFN-alpha B/D hybrids against various human tumor lines of different histological origin and to determine whether any of the hybrid molecules possessed immunomodulating activity that could active antitumor properties in peripheral blood monocytes of normal donors. Hybrids with the B domain at the NH2 terminal end exhibited higher activity for antiviral activity and a higher level of direct antitumor antiproliferative activities as compared with hybrids with the D domain at the NH2 terminal end. The positive hybrids were directly cytostatic to melanoma, glioblastoma, renal carcinoma, colon carcinoma, and prostatic carcinoma cells. Tumor cell sensitivity to IFN-alpha hybrids was independent of sensitivity to IFN-gamma or to Adriamycin. The growth of a normal cell line (human embryo fibroblast) was unaffected by IFN-alpha hybrids but was completely arrested by Adriamycin. Some of the IFN-alpha hybrids were also cytostatic to mouse melanoma, lung carcinoma, and fibrosarcoma cell lines, albeit at lower levels than they were to human cells. The incubation of monocytes with IFN-alpha hybrids with the B domain at the NH2 terminal end was also associated with marked antitumor cytotoxicity. Kinetic studies, however, indicated that this activity was attributable to IFN-alpha carried on monocytes and acting directly on tumor cells. We conclude that recombinant human IFN-alpha B/D hybrids possess potent direct antiproliferative activity against a large variety of human tumor lines.

DBA/2 mice transplanted with the high metastatic syngeneic lymphoma variant ESb can be successfully treated by a combination of surgery and active-specific immunotherapy (ASI). The ASI procedure was applied postoperatively and involved vaccination either (1) with inactivated ESb tumor cells which had been modified by incubation with a low dose of Newcastle Disease Virus (NDV) or (2) with mutagenesis-derived immunogenic tumor variants. The analysis of the immune status of spleens from tumor-bearing or tumor-immune mice revealed important differences. The activation of tumor-specific cytotoxic T-lymphocyte precursors (CTLP) from mice with metastasis required stimulation with the specific antigen plus additional helper factors (IL-2 or NDV). The importance of second signal immune stimulation for the activation of sensitized tumor-specific CTLP in tumor-bearing mice is underlined.