[Systemic therapy approaches in patients with bone metastases of urogenital malignancies]. / Systemische Therapieansätze bei Knochenmetastasen urogenitaler Tumoren.

Bone metastases develop commonly in patients with a variety of urogenital malignancies and are a major cause of morbidity and diminished quality of life in a significant proportion of urogenital carcinoma patients. For example, bone metastases occur in approximately 80% of patients with hormone-refractory prostate cancer and in approximately 25% of patients with renal cell carcinoma. A sufficient and early therapy is crucial since adequate therapy can lead to significant improvements in pain control and function and maintain skeletal integrity. The effective treatment of bone metastases requires multidisciplinary cooperation between urologists, oncologists, surgeons, nuclear medicine physicians and radiation oncologists. Analgesic measures, bisphosphonates, radionuclides, radiation therapy as well as surgical procedures are available. This review will focus mainly on the role of analgetics, bisphosphonates, radionuclides and radiolabelled bisphosphonates in the treatment of bone metastases.

Clinical value of transrectal ultrasound in the diagnosis of suspected neoplasia in the small pelvis.

PURPOSE: In daily clinical practice, it is challenging to accurately diagnose suspected neoplasias in the small pelvis by minimal invasive means, and CT-guided biopsy is often limited in its feasibility. The aim of our study was to evaluate whether transrectal ultrasound (TRUS)-guided biopsy can verify suspected neoplasias in the small pelvis histologically. MATERIAL AND METHODS: The study population consisted of 12 patients who underwent biopsy of suspected malignancy in the pelvis by TRUS. All patients had clinical signs of an advanced tumour stage and in all cases, biopsy utilising computerised tomography (CT scan) had been unsuccessful despite of a documented lesion on CT scan or magnetic resonance imaging. For the TRUS guided biopsy, a commercially available 3-dimensional 7.5-MHz-probe was used (Combison 530 D, GENERAL ELECTRIC, Milwaukee, USA). The probe was armed with an 18 G biopsy gun. RESULTS: In all patients, the suspected lesion was easily detectable by TRUS, and tissue for verification of the malignant origin of the lesions could be collected under real-time TRUS with only 2 patients needing anaesthesia. The biopsy cores were of excellent quality and adequate for conclusive pathological diagnosis. 6 cases of lymph node metastases of a transitional cell carcinoma were detected. 1 case of extended node metastasis in prostate cancer, 1 paravesical manifestation of recurrent cervical cancer, 1 metastasis of a paravesically infiltrating colon cancer and 2 cases of paravesical metastases of a gastric cancer were also diagnosed. In one case, extragenital endometriosis could be diagnosed. CONCLUSION: Based on our experience it can be stated that TRUS-guided biopsy is a reliable diagnostic tool for verification of the neoplastic origin of suspected masses in the small pelvis. In all cases with a history of unsuccessful CT guided biopsy, sufficient tissue cores for conclusive histology could be collected with our technique, and surgical exploration could be avoided. This technique is minimally invasive, without radiation exposure, well tolerated under analgesia, time efficient and cheap.

[TMPRSS2-ETS gene fusion in prostate cancer]. / Die TMPRSS2-ETS-Genfusion beim Prostatakarzinom.

BACKGROUND: Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. Using a novel bioinformatics approach, our group recently described a novel gene fusion in PCa. This fusion involves the androgen-regulated gene TMPRSS2 and so far three members of the ETS family of transcription factors already described as rearranged in the Ewing's family of tumors. By analogy, fusion status in prostate cancer may determine clinical outcome and secondary genetic alterations as witnessed in Ewing's tumors. MATERIAL: These novel gene fusions occur in the majority of prostate cancers identified by PSA screening and are the driving mechanism for overexpression of the three members of the ETS transcription factor family, either ERG (21q22.3), ETV1 (7p21.2), or ETV4 (17q21). Considering the high incidence of prostate cancer and the high frequency of this gene fusion, the TMPRSS2-ETS gene fusion is the most common genetic aberration so far described in human malignancies. RESULTS: So far, this is the only gene rearrangement in any of the most prevalent cancers. As confirmed by other groups, we demonstrated that, within the group of ETS transcription factors, ERG is the most common fusion partner of the ETS genes with TMPRSS2. This gene fusion is considered to be an early event in PCa development. Emerging data suggest that gene fusion PCa demonstrates a distinct clinical course and thus support its use as a diagnostic test and prognostic biomarker. Also similar to the Philadelphia chromosome in chronic myelogenous leukemia (CML), the gene fusion in prostate cancer has potential as an important candidate for the development of targeted therapy.

[Ureteral stricture after extracorporeal shock wave lithotripsy. Case report and overview of the spectrum of rare side effects of modern ESWL treatment]. / Ureterstriktur nach extrakorporaler Stosswellenlithotripsie. Kasuistik und Ubersicht über das Spektrum seltener Nebenwirkungen der modernen ESWL-Therapie.

Extracorporeal shock wave lithotripsy (ESWL) is considered a very safe and noninvasive procedure for the treatment of urolithiasis. Achievements in the technical development of recent decades resulted in a continuous reduction of side effects. One of our patients, a woman with cystinuria, developed a temporary ureteral stricture after several sessions of ESWL. Encouraged by this observation we set out to explore--based on a MEDLINE literature search--published reports of more severe side effects observed in modern ESWL therapy. Besides hydronephrosis and renal colic the most common side effects were renal and perirenal hematomas in up to 4% in the larger series. Uncommon extrarenal complications are described mostly in case reports, which are also outlined in this report. The injury of visceral organs (liver, spleen, gut, pancreas) was published most frequently. A rupture or dissection of an abdominal aortic aneurysm as an outstanding serious complication was also reported several times. Taking obvious and well-known contraindications into consideration and carefully preparing the patients for the therapy (i.e., checking hemostasis, drug history), ESWL is a very safe procedure with a low risk of serious complications. Yet, postoperative clinical and ultrasound monitoring seems to be essential especially with respect to the increasing numbers of outpatient procedures.

The role of radical prostatectomy in patients with clinically localized prostate cancer and a prostate-specific antigen level >20 ng/ml.

OBJECTIVES: To determine the outcome of patients with a serum prostate-specific antigen (PSA) level >20 ng/ml that underwent radical prostatectomy (RP). METHODS: We retrospectively reviewed the medical records of 147 patients who underwent RP for clinically localized prostate cancer with a pre-treatment PSA (PSApt) >20 ng/ml. Fifty-two patients had positive pelvic lymph nodes and were excluded from analysis. Of 95 patients remaining, 15 were lost to follow-up. Therefore, the study group included 80 patients. The end points for this analysis were biochemical relapse-free survival (bRFS), surgical and post-operative complications and urinary continence. PSApt, pathological grade, surgical margin status, age, clinical stage and immediate androgen ablation were evaluated in a multivariate analysis regarding bRFS. RESULTS: Forty-nine resected specimens (61.2%) were pathologically classified as pT3 or pT4. After a mean follow-up of 64 months, the estimated 5-year bRFS rate was 58% for the overall group. Immediate androgen ablation was the only independent prognostic factor for biochemical relapse (P=0.001). Concerning the 21 patients who received an immediate androgen ablation after RP, the estimated 5-year bRFS rate was 92%. Complete urinary continence was achieved in 76.5% of patients. Early complications occurred in 13 patients (16.2%). CONCLUSIONS: Clinically localized prostate cancer with a PSApt >20 ng/ml is considered as having a poor prognosis. However, RP performed in these patients led to an acceptable morbidity and good functional results. Immediate adjuvant hormonal therapy seems mandatory in this setting to improve bRFS.

[Translational research in renal cell cancer. Illustrated by the example of the vascular endothelial growth factor pathway]. / Translation molekularer Zusammenhänge in die klinische Anwendung. Dargestellt am Beispiel des Vascular-Endothelial-Growth-Factor- (VEGF-)Pathway.

For patients with metastatic renal cell cancer (RCC), therapeutic options after cytokine failure are rather limited. There is a considerable need to identify new substances for systemic therapy. Due to upregulation after the loss of a functional von Hippel Lindau gene product, the vascular endothelial growth factor (VEGF) pathway is a promising target for a molecular based therapy. Over the last few years, therapeutic agents have been developed which inhibit this pathway at various levels. Here, we provide an overview of the molecular background and currently used drugs which have entered clinical trials in the setting of metastatic RCC disease. Until now, the results from early clinical trials are very promising, however, the best schedule, dosage, potential combination regimens, as well as long time efficacy, are still to be determined.

Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer.

In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 microg l(-1) at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients.

Changing diagnostic and therapeutic concepts in high-flow priapism.

High-flow priapism (HFP) is defined as pathological increased arterial influx into the cavernosal bodies. Since 1960, 202 cases have been published in the literature. This study evaluates the effect of the changing diagnostic and therapeutic concepts. The data of 202 cases of HFP was evaluated regarding diagnostic and therapeutic procedures and long-term results. Success was defined as restored erectile function without recurrent priapism. The major etiology of HFP is trauma, especially in children or young adults; in older men, HFP is a rare event mainly caused by malignoma. Cavernosal blood-gas analysis, color-Doppler ultrasound and angiography were the most effective diagnostic tools to distinguish high- from low-flow priapism. The success rate was 20% for shunt operations and 89% for arterial embolization. In conclusion, embolization was effective in the majority of cases of traumatic HFP, while shunt surgery remained disappointing. For HFP caused by inherited diseases and malignoma conservative therapy is mandatory.

Comparison of external radiation therapy vs radical prostatectomy in lymph node positive prostate cancer patients.

INTRODUCTION: Treatment options for lymph node positive prostate cancer are limited. We retrospectively compared patients who underwent external radiotherapy (ERT) to patients treated by radical prostatectomy (RPX). MATERIALS AND METHODS: A total of 102 lymph node positive patients from the RPX series at Ulm University were evaluated. In all, 76 patients received adjuvant androgen withdrawal as part of their primary treatment. In the ERT group, 44 patients were treated at the University of Michigan using a fractionated regimen. Of these, 21 patients received early adjuvant hormonal therapy. Patients with neoadjuvant therapy before RPX or ERT were excluded. RESULTS: In the RPX group, PSA nadir (nadir < or = 0.2 vs > 0.2 ng/ml) showed a strong association with outcome. In the ERT group, pretreatment PSA was an independent predictor of outcome (P = 0.04) and patients with adjuvant hormonal therapy had a significant longer recurrence-free interval compared to patients without adjuvant therapy (P = 0.004). Comparing only patients with adjuvant hormonal treatment after cancer-specific therapy, the ERT-treated patients had a borderline longer PSA recurrence-free survival time compared to the RPX-treated patients (P = 0.05). CONCLUSIONS: In case of positive lymph nodes, RPX and ERT might be considered and need to be explained to the patient. For future treatment decisions, the presented findings and a potential survival benefit need to be evaluated in a larger prospective setting.

[Tissue microarrays. High-throughput procedures to verify potential biomarkers]. / Tissue-Microarrays. Ein Hochdurchsatzverfahren zur Verifizierung potenzieller Biomarker.

High-throughput molecular screening tools have created a need for equally rapid means to verify potential biomarkers. Tissue microarray (TMA) technology facilitates effective analysis on the protein level. Hundreds of 0.6-mm-diameter tissue samples are placed on a single standard glass slide. This approach allows analysis with different in situ methods of all tissue samples in one experiment under standardized conditions. TMAs are not only perfectly suited for molecular epidemiologic studies if applied on multitumor arrays composed of a variety of tumor entities, but they are also used for tumor-specific investigations of molecular markers. In this report the technical aspects of TMAs as a miniaturized high-throughput technology are described. We further demonstrate how the TMA technique will help to accelerate the transition from basic research to clinical application in prostate cancer disease.

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer.

Histone deacetylase inhibitors (HDACs) are known to exhibit antiproliferative effects on various carcinoma cells. In this study, the in vivo efficiency of two HDACs, sodium butyrate and tributyrin, on prostate cancer growth inhibition were investigated. To gain an insight into the possible underlying pathways, cell culture experiments were performed focusing on the expression of p21, Rb and c-myc. For in vivo testing, prostate cancer cell lines (PC3 and TSU-Pr1) were seeded on the chorioallantois membrane (CAM) and implanted in a xenograft model using nude mice. Standard Western blot analysis was performed for protein expression of p21, Rb and c-myc in HDAC-treated vs untreated prostate cancer cells. Both sodium butyrate and tributyrin had a considerable treatment effect on microtumours on the chicken egg at already very low concentrations of 0.1 mM. Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3. In the mouse model, there was almost no difference between sodium butyrate and tributyrin. In untreated animals the tumours were almost double the size 4 weeks after implantation. Tumours of the treatment groups had a significantly lower percentage of Ki-67-positive-stained nuclei. As demonstrated by Western blot analysis, these effects seem to be independent of p53 status and a pathway via p21-Rb-c-myc is possibly involved. In this study we have demonstrated a substantial in vivo treatment effect, which can be induced by the application of sodium butyrate or the orally applicable tributyrin in human prostate cancer. The given results may provide the rationale to apply these drugs in well-controlled clinical trials in patients being at high risk of recurrence after specific therapy or in patients with locally or distant advanced prostate cancer.

Association between the clinical presentation and epidemiological features of familial prostate cancer in patients selected for radical prostatectomy.

OBJECTIVE: We evaluated if epidemiological features of familial prostate cancer are associated with certain clinical or histopathological characteristics of the disease. METHODS: 463 German patients with familial prostate cancer who underwent radical prostatectomy were stratified according to several epidemiological criteria: (1). the apparent mode of disease transmission, (2). the average age of onset and (3). number of affected relatives/family, (4). whether or not they met the Johns Hopkins criteria of hereditary prostate cancer. The variables analysed included the Prostate Specific Antigen (PSA) and the digital rectal examination at diagnosis, histopathological characteristics of the prostatectomy specimen and relapse free 5-year survival rates. These characteristics were compared within the subsets of familial patients and compared to 492 control patients with sporadic prostate cancer. RESULTS: Age of onset was the only clinical parameter differentiating familial and sporadic prostate cancer. Otherwise there was no association between epidemiological features of familial predisposition and the clinical presentation or outcome of the disease. CONCLUSIONS: Familial and sporadic prostate cancer seem to be the same disease. Alternatively it may be concluded that the common epidemiological features of familial prostate cancer are not useful to tell tumours that are based on inherited susceptibility apart from those that are not. Whether hereditary prostate cancer is clinically distinct from sporadic forms cannot be determined before the underlying genetic alterations are identified.

Colour Doppler ultrasound in vesicovaginal fistulas.

The purpose was to evaluate the feasibility of diagnosing vesicovaginal fistulas by colour Doppler ultrasound with contrast media. Twelve consecutive patients were examined by vaginoscopy, methylene blue test, cystogram and cystoscopy. For ultrasound examination, the bladder was filled with saline. Then diluted contrast media (Levovist) was instilled. Colour Doppler ultrasound revealed a jet phenomenon through the bladder wall toward the vagina, proving the existence of the fistula. Eleven patients had vesicovaginal fistulas, one patient a vesicoureterovaginal fistula. Colour Doppler ultrasound had correct results in 11 of 12 patients (92%). In follow-up examinations of four patients during a prolonged drainage of the bladder, we could correctly demonstrate the closure of one fistula. Colour Doppler ultrasound with contrast media is a new useful diagnostic tool in the evaluation and follow-up of vesicovaginal fistulas. It is less invasive than cystoscopy and needs no radiation exposure. The examination is well tolerated by the patients.