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We report the case of a 61-year-old man, with a rare combination of two advanced urological tumors: a concomitant spread of an adenocarcinoma beyond the kidney and a urothelial carcinoma beyond the bladder. We simultaneously performed a primary curative prostatovesiculectomy and a nephroureterectomy on the right with ileal neobladder. To our knowledge, a case report of concomitant spread of an adenocarcinoma beyond the kidney (pT3 pN0 M0 G3) and a urothelial carcinoma beyond the bladder (pT3a pN0 M0 G3) with subsequent curative therapy has thus far not been published. A combination of the two diseases described here is obviously a remarkable rarity.

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.

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.

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.

Intercellular adhesion molecule-1 (ICAM-1) is the natural ligand of the T-lymphocyte adhesion molecule LFA-1 (lymphocyte-function-associated antigen-1). ICAM-1 is involved in target cell recognition by T-lymphocytes, LAK cells and natural killer cells. The molecule has also been detected on a variety of normal cells and on human tumors. Renal cell carcinoma (RCC) is one of the few tumors that respond to immunotherapy, but clinical results are generally disappointing. We therefore analyzed, by immunohistochemistry, the expression of ICAM-1 in pairs of normal kidneys, RCC, and RCC metastases. Moreover, serum ICAM-1 was determined in RCC patients and compared with surface expression of cell-bound ICAM-1. Strong glomerular expression of ICAM-1 was observed in all specimens of normal kidney examined. Proximal tubuli were weakly stained in the majority of specimens. Of the tumors, 80% stained positive for ICAM-1. Although ICAM-1 was detected on the majority of extrarenal tumor specimens examined, staining was generally weaker in the metastases. Patients without metastases at initial presentation more frequently expressed ICAM-1 in their primary tumors than did patients with metastases. Levels of serum ICAM-1 (sICAM-1) were significantly higher in RCC patients than in controls with non-malignant renal diseases. Patients with an unfavorable prognosis, e.g. with advanced tumor stage or metastasis at initial presentation, had higher levels of sICAM-1 than patients with low-grade and/or low-stage tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Frozen sections of primary and metastatic human renal cell carcinoma (RCC) were analyzed for the expression of endogenous binding sites for carbohydrates. Fluorescent neoglycoproteins, carrying chemically linked carbohydrate residues on bovine serum albumin as a carrier protein, were applied to 44 primary tumor specimens. In the majority of specimens, accessible binding sites with specificity for maltose and N-acetylgalactosamine were detected. In specimens of normal kidney no specific binding of carbohydrate ligands was observed under these experimental conditions. Specimens of both the primary tumor and a metastasis were available in 10 cases. When the expression of specific binding sites of primary tumors and metastases was compared, the respective patterns were similar with no clear gain or loss of certain lectins in the metastases. We conclude that binding sites with specificity for maltose and N-acetylgalactosamine are present on human RCC and their corresponding metastases.

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.

Metastasis to distant organs is the principal cause of death from renal cell carcinoma (RCC). No commonly accepted therapy is available for disseminated RCC at present. Immunotherapy is a mode of therapy that either interferes with the immune system or makes use of drugs that have been derived from soluble mediators of the immune system. Several lines of evidence suggest that combinations of genetically engineered cytokines (e.g. interleukin-2 and interferon alpha) may be particularly active in the treatment of advanced RCC. There are two major rationales for considering immunotherapy for RCC: (1) there is currently no other therapy available, and (2) there is hardly any innovative approach besides immunotherapy. Still, immunotherapy is far from being a standard therapy for disseminated RCC.