[Inhibitors of the androgen receptor N­terminal domain : Therapies targeting the Achilles' heel of various androgen receptor molecules in advanced prostate cancer]. / Inhibitoren des Androgenrezeptor-N-Terminus' : Zielgerichtete Therapien gegen die Achillesferse verschiedener Androgenrezeptormoleküle im fortgeschrittenen Prostatakarzinom.

Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR. The following review delineates recent progress in the development of AR inhibitors that do not depend on androgen binding and represent a putative third generation of AR inhibitors.

[A critical assessment of phytotherapy for prostate cancer]. / Eine kritische Bewertung der Phytotherapie des Prostatakarzinoms.

Prostate cancer patients increasingly use complementary and alternative medicines to support the body's immune system in addition to conventional treatment to minimize morbidity associated with conventional treatment, to enhance the quality of life, and ultimately in the hope to cure cancer when conventional treatment fails. As there is a large variety of phytomedicines promoted as potential treatment for prostate cancer, the aim of this review was to differentiate between preventive and therapeutic approaches and evaluate which phytochemicals might be suited for therapy of prostate cancer. Therefore, preclinical in vitro and in vivo data as well as clinical trials with phytosubstances such as genistein, lycopene, epigallocatechin gallate, resveratrol, and mistletoe were assessed. The presented data show that at present there is no clinical evidence that phytochemicals might have a therapeutic use in prostate cancer in relation to reduction of tumor progression or improved survival. The question about an improved immune function or quality of life remains open. Potentially the use of phytochemicals could play a role in a preventive setting.

Soy isoflavone genistein in prevention and treatment of prostate cancer.

Dietary habits and incidence of prostate cancer (PCa) are very different in several parts of the world. Among the differences between Eastern and Western diets is the greater intake of soy in the Eastern cultures. This might be one factor contributing to a lower incidence of PCa in Asian men. Many studies using PCa cells and animal studies of chemical carcinogenesis have shown that a wide range of dietary compounds have cancer chemopreventive potential. Therefore, the interest in nutrition-based approaches for prevention and treatment of PCa is increasing. We reviewed all experimental preclinical in vitro and in vivo data as well as clinical trials performed with soy isoflavone genistein for prevention and treatment of PCa. The preclinical data for genistein presented in this review show a remarkable efficacy against PCa cells in vitro with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, seemingly well-conducted animal experiments support the belief that genistein might have a clinical activity in human cancer therapy. However, it is difficult to make definite statements or conclusions on clinical efficacy of genistein because of the great variability and differences of the study designs, small patient numbers, short treatment duration and lack of a standardized drug formulation. Although some results from these genistein studies seem encouraging, reliable or long-term data on tumor recurrence, disease progression and survival are unknown. The presented data potentially allow recommending patients the use of genistein as in soy products in a preventive setting. However, at present there is no convincing clinical proof or evidence that genistein might be useful in PCa therapy.

New agents for treatment of advanced transitional cell carcinoma.

The prognosis for any patient with progressive or recurrent invasive transitional cell carcinoma remains poor. In this context, the focus of clinical research in these invasive cancers concentrates on identifying systemic treatment options and new agents in order to improve survival of patients. Cisplatin-based chemotherapy is standard treatment of patients with metastatic urothelial cancer; however, despite regimens as the cisplatin-gemcitabine combination, the overall response rates vary between 40% and 65%, with complete response in 15%-25% with survivals up to 16 months. This survival is frequently achieved with severe and life-threatening side effects. None the less, almost all responding patients relapse within the first year; therefore, the need for development of new and tolerable agents is urgent. This review highlights some new active chemotherapeutic as new platinum compounds (oxaliplatin, lobaplatin), gallium nitrate, ifosfamide, the antifolates piritrexim and pemetrexed (Alimta, LY231514), vinflunine and molecular targeting agents such as farnesyltransferase inhibitors (lonafarnib, R115777, SCH66336), ribozyme (RPI.4610), histone deacetylase inhibitor (CI-994) and monoclonal antibodies (epidermal growth factor receptor, Her 2/neu).

Superselective embolization of arterial bleeding as a late complication 3 months after nephron sparing surgery for renal cell carcinoma.

To our knowledge, this is the first case of an arterial bleeding as a late complication 3 months after nephron sparing surgery of renal cell cancer, presumably originating from an arteriocalyceal fistula. Superselective embolization of the feeding arterial branch was chosen for treatment of the hemorrhage and proved successful. The high efficacy of superselective embolization as a minimally invasive procedure in this and other cases of bleeding Vessels should be the preferred method instead of open surgery.

Preclinical evaluation of a radiosensitizing effect of gemcitabine in p53 mutant and p53 wild type bladder cancer cells.

OBJECTIVES: Despite clinical use, the radiosensitizing effect of gemcitabine (2'2'-difluorodeoxycytidine) in human transitional cell carcinoma (TCC) has not been shown to date. We investigated gemcitabine as a radiosensitizer for human TCC cells. METHODS: Monolayer cultures of RT112 (G1, p53 wild type), RT4 (G1-G2, p53 wild type), T24 (G3, p53, mutant type), and SUP (G4, p53 mutant type) cells were incubated in medium with gemcitabine. Electron beam radiation was applied alone, simultaneous, or 3, 6, 12, and 24 hours after gemcitabine. Jurkat leukemia cells were used as controls for radiation toxicity. Cell survival was determined 6, 12, 24, 48, and 72 hours after radiation by microculture tetrazolium assay. DNA damage was evaluated by flow cytometric assessment of poly(ADP-ribose) polymerase, and apoptosis was determined by terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labeling and flow cytometric assessment after annexin-V and propidium iodide labeling. RESULTS: In all TCC cell lines, radiation alone caused only little and insignificant growth inhibitory effects at 10 Gy. Gemcitabine alone had a dose-dependent cytotoxic and apoptosis inducing effect on all TCC cell lines independent of p53 status. Assays combining radiation with gemcitabine in different dose and time schedules demonstrated no radiosensitizing effect in TCC cells. CONCLUSIONS: Gemcitabine is effective in TCC cell lines independent of p53 status. A radiosensitizing effect could not be demonstrated. Again, p53 status was not predictive of the radioresponse in the bladder cancer cell lines. Clinical studies with gemcitabine and radiotherapy might nevertheless yield different results but should be performed with utmost caution.

Gemcitabine monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma - prognostic factors for response and improvement of quality of life.

OBJECTIVES: i) To evaluate objective response, toxicity, and quality of life (QoL) of gemcitabine monotherapy as second-line treatment in patients with cisplatin-refractory, metastatic transitional cell carcinoma (TCC). ii) To assess prognostic parameters for response to treatment and for improvement of QoL parameters. PATIENTS AND METHODS: 30 patients were prospectively enrolled in this open-label, nonrandomized multicenter phase II trial. Patients received up to 6 courses of gemcitabine monotherapy (1,250 mg/m(2) on day 1 and 8 of a 21-day course). 28 of 30 patients were available for response evaluation. RESULTS: Objective response (OR) was seen in 3/28 (11%) of patients (2 complete remissions, 1 partial remission). The mean time to progression (TTP) was 4.9 +/- 3.5 months and mean disease-specific survival time was 8.7 +/- 4.7 months. 13 of 28 patients did not progress (OR + 10 stable diseases), and TTP (8.0 +/- 2.7 months, p < 0.001) as well as survival time (10.2 +/- 3.8 months, p < 0.05) differed significantly from those who showed progressive disease within 18 weeks of treatment. Pain values significantly improved in the group of responders from 4.3 +/- 1.9 to 5.8 +/- 1.3 points (p < 0.05). Response to cisplatin pretreatment was the best prognosticator for the response to gemcitabine. CONCLUSIONS: Gemcitabine monotherapy as second-line treatment is justified in patients with metastatic TCC who are refractory to cisplatin treatment. Patients with initially OR to cisplatin benefit most from second-line treatment. QoL remains stable during treatment, and pain improves especially in patients with bone metastases.

Soluble Fas and Fas-ligand in bladder cancer in vitro and in vivo.

Circulating soluble Fas (sFas) and expression of Fas-ligand on cancer cells are mechanisms of immune escape. The aim of the present study was to investigate expression and production of Fas and Fas-ligand on bladder cancer cell lines of different grade as a basic mechanism of their secretion in vivo. sFas and sFas-ligand serum levels of patients with different stage of bladder cancer were examined to determine the possible clinical use of these molecules as tumor markers. Bladder cancer cell lines RT4 (G1), RT112 (G1), T24 (G3) and SUP (G4) were analyzed by flowcytometry for Fas and Fas-ligand expression. To determine if the Fas-ligand gene is transcribed in these bladder cancer cell lines, RT-PCR was performed on mRNA extracted from these cell lines. Production of sFas and sFas-ligand was examined in cell culture supernatants of the cancer cells as well as in the serum of 62 patients with bladder cancer by a specific ELISA test. We demonstrate that Fas is expressed in similar levels on all human bladder carcinoma cell lines. In T24 (G3) and SUP (G4) cell lines we were able to detect the Fas-ligand protein, whereas no Fas-ligand protein could be found in RT4 and RT112 (G1) cells. Fas-ligand mRNA was expressed in all bladder cancer cell lines. Furthermore, all bladder cancer cell lines produce sFas but no sFas-ligand in spite of mRNA expression. The range of sFas levels in the serum of all patients with bladder cancer was large and did not show a correlation to the histopathological stage of bladder cancer. Although there is in vitro evidence that sFas and Fas-ligand play a role in bladder cancer, no correlation between the sFas and s Fas-ligand serum levels and the histopathological stage of bladder cancer could be found. Therefore, serum sFas and sFas-ligand have to date limited clinical relevance.

Adjuvant chemotherapy in stage I and stage II testicular cancer.

Adjuvant chemotherapy in low-stage testis cancer is an accepted treatment option for two clinical situations: (1) chemotherapy after complete removal of the primary tumor by orchidectomy without clinical evidence of metastasis (clinical stage I), and (2) chemotherapy after complete surgical removal of non-seminomatous retroperitoneal metastases up to 5 cm in greatest transverse diameter by retroperitoneal lymph node dissection in clinical stage II. Aim of treatment is the prevention of tumor recurrences. The risk of recurrence depends on the type and stage of disease and ranges from 16% (clinical stage I seminoma) to 50% (pathological stage II B non-seminoma). Thus, 50-84% of patients receive adjuvant treatment unnecessarily. Prognostic factors have been developed in each tumor entity to tailor treatment to patients with high risk of recurrence.

Bladder cancer cells acquire competent mechanisms to escape Fas-mediated apoptosis and immune surveillance in the course of malignant transformation.

Mechanisms of resistance against Fas-mediated cell killing have been reported in different malignancies. However, the biological response of immune escape mechanisms might depend on malignant transformation of cancer cells. In this study we investigated different mechanisms of immune escape in 2 well-differentiated low-grade (RT4 and RT112) and 2 poorly differentiated high-grade (T24 and TCCSUP) bladder cancer cell lines. Fas, the receptor of Fas-ligand, is expressed and shedded by human transitional bladder carcinoma cell lines RT4, RT112, T24 and TCCSUP. Cytotoxicity and apoptosis assays demonstrate that in spite of the Fas expression, poorly differentiated T24 and TCCSUP cells are insensitive towards either recombinant Fas-ligand or agonistic apoptosis-inducing monoclonal antibody against Fas. In poorly differentiated T24 and TCCSUP cell lines we were able to detect marked Fas-ligand protein by flow cytometry and Western blot analysis. In grade 1 RT4 and RT112 cells only minor expression of Fas-ligand possibly because of proteinase action. Fas-ligand mRNA translation or post-translational processing seems to be regulated differentially in the cancer cell lines depending on malignant transformation. In co-culture experiments we show that poorly differentiated cells can induce apoptosis and cell death in Jurkat cells and activated peripheral blood mononuclear cells. This in vitro study suggests that bladder cancer cells can take advantage of different mechanisms of immune evasion and become more competent in avoiding immune surveillance during transformation to higher-grade malignant disease.

Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in urological malignancies.

Several studies suggest that cellular adhesion molecules (CAM) play a role in cancer progression and metastasis. To evaluate the role of these molecules as possible tumor markers in patients with urological malignancies, we examined the serum levels of intercellular cell adhesion molecule-1 (ICAM-1), vascular cellcular adhesion molecule-1 (VCAM-1) and E-selectin in patients with renal cell-, bladder-, prostate- and testicular cancer. Serum levels of 237 patients with urological cancers, renal cell carcinoma (n = 47), bladder cancer (n = 81), prostate cancer (n = 87) and testicular cancer (n = 22) and a group of 41 patients with benign prostate hyperplasia (BPH) as well as a 42 healthy control persons were examined for CAMs by specific ELISA tests. Serum CAM concentrations of all tumor patients were compared with controls and within the group according to T stage, N stage, tumor grade and extent of distant metastasis. Our results demonstrate that ICAM-1 and VCAM-1 serum levels are not stage dependently elevated; in contrary, they demonstrate a wide range and are highly variable throughout the different cancer types. In renal cell cancer and in bladder cancer, there is a significant difference for ICAM-1 between controls and T3 and T4 and metastatic cancers. A similar difference was found for VCAM-1, however not for E-selectin in any tumor group. Testicular cancer and prostate cancer did not demonstrate any difference in CAM serum levels between patients with tumors and controls. In metastatic renal cell-, bladder- and prostate cancer, the serum levels of ICAM-1 and VCAM-1 showed a tendency to correlate with the extent of metastatis although no statistical difference between patients with a single metastatic lesion and patients with multiple lesions could be demonstrated. The results of this study implicate a rather limited role of cellular adhesion molecules. Despite of significant ICAM-1 or VCAM-1 serum levels in some locally advanced tumors or metastatic disease, this observation does not provide enough relevant clinical information for use as tumor markers.

Hydronephrosis after aorto bifemoral graft surgery: a marker for late graft complications.

Ureteral obstructions are serious late complications after aortoiliac reconstructive vascular surgery, which lead to loss of kidney function if they remain untreated. One case report serves to describe the incidence, aetiology, clinical presentation and treatment options of an obstructive uropathy following graft surgery. Hydronephrosis due to a ureteral obstruction is considered as a "marker" of graft complication. Therefore, ultrasound examination and close follow-up beyond 1 year are recommended in all patients who undergo aortoiliac surgery.

Squamous cell carcinoma of the penis.

Squamous cell carcinoma of the penis is a rare disease in Western countries. In geographical locations where infantile circumcision is not routinely practised and genital hygiene is poor, penile cancer may comprise 10-20% of all malignancies. Superficial tumours (Ta-Tl) should be treated with organ-preserving therapy. Partial of total penectomy is recommended for invasive penile carcinoma (stage T2 or higher). Currently, management of the ilioinguinal lymph nodes is controversial. The value of radiation therapy and chemotherapy is still uncertain; these treatments are only palliative therapy modalities.

Urinary levels of monocyte chemo-attractant protein-1 correlate with tumour stage and grade in patients with bladder cancer.

OBJECTIVE: To determine if the chemokine monocyte chemo-attractant protein-1 (MCP-1) is produced locally in patients with bladder cancer and to analyse a possible correlation between tumour stage, grade and metastatic spread, and the urinary and systemic levels of MCP-1. PATIENTS SUBJECTS AND METHODS: Urine and serum samples were obtained from 60 patients with bladder cancer and 20 control subjects. Tumour stage, grade, metastasis and nodal status were assessed. MCP-1 levels in serum and urine were determined using a sandwich enzyme-linked immunosorbent assay. Two transitional cell cancer cell lines (grade I and grade III) were analysed for MCP-1 production under normal and nutritive-stress cell culture. RESULTS: The correlation of urinary MCP-1 levels with tumour stage, grade and distant metastasis was highly significant. Patients with stage T2-T4 bladder cancer had three to fourfold higher mean MCP-1 concentrations (pg/mL) in their urine than those with T1 stage tumours or than the controls (controls 260; T1 359; T2 967; T3 917; T4 1829; P < 0.005). A tumour grade of > GI and the existence of distant metastasis (M1) also correlated significantly with higher urinary MCP-1 levels (GI 373; GII 661; GIII 1111; M0 644; M1 1379; P < 0.05). No differences in circulating serum MCP-1 level were detected between controls and patients. The low-grade (GI) RT4 bladder cancer cell line produced only traces of MCP-1, which did not change under nutritional stress; in contrast, the highly malignant T24 bladder cancer cell line (GIII) spontaneously secreted large amounts of MCP-1 (approximately 7000 pg/mL) which increased under nutritive stress to 13,000 pg/mL. CONCLUSION: MCP-1, as a potent monocyte chemo-attractant to tumour sites, is probably produced by bladder cancer cells; MCP-1 levels in the vicinity of the tumour (i.e. urine) correlate significantly with TNM stage and grade. As has already been shown in other neoplasms, the resulting monocyte/macrophage infiltrate possibly facilitates tumour neovascularization and tissue invasion. Therefore, MCP-1 levels in the urine of patients with bladder cancer may be a prognostic marker for the natural course of the disease, and modulation of this chemokine might be a future therapeutic approach for adjuvant treatment of bladder cancer.