Prevention strategies for prostate cancer.

Through the last decade consideration of the role of vitamins and minerals in primary prevention of genitourinary tumors has dramatically changed. Despite all efforts efficacy of a specific compound has not been proven, so far. In consequence, recommendations for a use of vitamins or other supplements with the intention of prostate cancer prevention should be avoided today. In contrast, there is some evidence that life style modification might be helpful: recent investigations suggest that smoking may be involved in prostate cancer carcinogenesis. In addition, there is evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet might not only prevent prostate cancer but also harbors additional beneficial effects on general health. This move from single compounds to more complex diets can be considered as a change of paradigm in prostate cancer prevention and could be the starting point of future epidemiological research. Disappointing findings with regards to nutritional cancer prevention contrast with a solid evidence concerning the efficacy of chemoprevention using 5a-reductase inhibitors: Long-term use of Finasteride and Dutasteride significantly reduces prostate cancer detection. Further candidate drugs are under investigation. However, translation of these findings into urological practice remains a matter of controversial discussion.

[Intraoperative frozen section diagnosis of the genitourinary tract]. / Intraoperative Schnellschnittdiagnostik des Urogenitaltrakts.

Up to now intraoperative frozen section, diagnosis has been of limited utility in urologic oncology. In the future, it may become more important due to a significant increase in the number of nerve-sparing operations performed for prostate cancer. Accuracy and benefit of intraoperative frozen sections depend both on a good communication between surgeons and pathologists as well as on a strict assessment of the need for surgery in the individual patient. In order to optimize cost-efficiency and to reduce the associated risks the indications for intraoperative frozen sections must be rigorously appraised. This report outlines clinically relevant indications for intraoperative frozen section diagnosis in tumors of the urinary tract, kidneys, prostate, testis and penis according to the most recent guidelines. The diagnostic scope and problems of this method are also discussed.

[Rational follow-up of non-muscle invasive bladder cancer]. / Rationale Nachsorge des nicht-muskelinvasiven Harnblasenkarzinoms.

BACKGROUND: Follow-up for non-muscle invasive bladder cancer (NMIBC) is a challenge for urologists that has not been finally resolved. The intensity of follow-up is based on the recurrence and progression behavior of the tumor as well as the patient's individual situation. MATERIALS AND METHODS: The following article focuses on the current data situation, the valid German S3 guideline and the available instruments for the detection of relapses and progression, taking into account tumor stages and degree of malignancy. RESULTS: Urethrocystoscopy, imaging and urine cytology are generally recommended, but the recommendations appear to be too extensive in the case of so-called intermediate risk profiles. Depending on the situation, urine markers could optimize follow-up, although results from prospective randomized studies are still pending. CONCLUSIONS: The current follow-up of NMIBC is invasive, carries the risk of side effects and increases costs. In the absence of scientific evidence, recommendations for follow-up for NMIBC are naturally based on expert opinion. In the opinion of the authors, overdiagnosis is currently taking place particularly in patients with an intermediate risk profile. The first prospective, marker-based studies are ongoing and will be helpful in the near future to improve the data situation relevant to urological practice.

[Chemoprevention of prostate cancer. Current status]. / Chemoprävention des Prostatakarzinoms. Stand der Dinge.

Fueled by the results from recently published large interventional trials the topic of chemoprevention of prostate cancer has increasingly attracted the interest of practicing urologists. In this analysis the term"chemoprevention" comprises all agents not included in regular food intake. If possible, the results from interventional studies were considered. Today, it must be accepted as evidence-based that chemoprevention of prostate cancer by 5alpha-reductase inhibition using finasteride is possible. Furthermore, there is increasing evidence that selective estrogen receptor modulators (SERMs) may also have preventive potential. Prospective interventional trials investigating these substances are currently underway. Considering the high incidence and the fact that the diagnosis of prostate cancer has serious impact on the future life of the respective individuals further scientific evaluation of chemoprevention of prostate cancer is mandatory.

[The Prostate Cancer Prevention Trial (PCPT). Relevance for clinical practice]. / Das "Prostate Cancer Prevention Trial" (PCPT). Die Bedeutung für den klinischen Alltag.

The Prostate Cancer Prevention Trial (PCPT) has been the first interventional trial directly aimed at the prevention of prostate cancer. A total of 18,882 men over 55 years with a PSA serum level less than 3.0 ng/ml were randomized to receive either the 5-alpha-reductase inhibitor finasteride 5 mg/day or placebo for 7 years. Despite a 25% reduction of prostate cancers in the treatment arm the results were discussed controversially. This criticism was mainly due to the observation of significantly more high-grade cancers in the finasteride group. Meanwhile, results of extensive follow-up analyses have been published suggesting that this finding is most likely due to optimized tumor detection in smaller glands. Further work-up demonstrated that PSA diagnosis and the histopathological examination were not compromised by finasteride. Furthermore, in addition to a decrease of prostate cancer the amount of prostatic intraepithelial dysplasia (PIN) was also reduced under finasteride. Future research must now aim at defining high-risk groups specifically profiting from chemoprevention with a 5-alpha-reductase inhibitor.

Hypomethylation of L1 LINE sequences prevailing in human urothelial carcinoma.

Alterations of DNA methylation were investigated in 6 urothelial carcinoma cell lines and 13 tumor tissues. The methylation of L1 LINE sequences was diminished in all cell lines (by 26 +/- 5%; range, 11-49%) and in most tumors (by 21 +/- 5%; range, 0-60%) compared to normal bladder mucosa. Hypermethylation of the calcitonin gene CpG island was restricted to cell lines and was not found in primary tumors, suggesting it had arisen during culture. In single-cell clones of a urothelial carcinoma cell line, both hypomethylation of L1 sequences and hypermethylation of the calcitonin gene persisted, indicating that they coexist within one cell. DNA methyltransferase expression did not correlate with the methylation status of the cell lines, but rather with histone H3 expression. Accordingly, it was down-regulated in quiescent cells. Aberrant expression of DNA methyltransferase is therefore not likely the cause for altered methylation patterns in urothelial carcinoma. L1 LINE hypomethylation seems to prevail in urothelial carcinoma and in this tumor might be useful for diagnostic or prognostic purposes.

Predisposition towards urolithiasis associated with the NQO1 null-allele.

The distribution of two alleles of the NQO1 gene encoding NADP(H):quinone oxidoreductase was studied in 140 urolithiasis patients and 271 control individuals. The minor allele encoding a protein lacking quinone reductase activity was significantly more frequent (q = 0.214) among these patients than in control individuals (P = 0.135) indicating an increased risk for kidney stone formation among heterozygotes (odds ratio 1.83, confidence interval 1.17-2.86) and homozygotes for the null-allele (odds ratio 2.97, confidence interval 0.78-11.33). Since NADP(H):quinone oxidoreductase is thought to participate in activation of vitamin K for protein gamma-carboxylation, decreased activity of the enzyme in heterozygotes or in null-allele homozygotes may disturb the post-translational modification of urinary calcium-binding proteins protective against kidney stone formation. The NQO1 null-allele might therefore be a determinant in enhanced risk of urolithiasis.

Increased frequency of a null-allele for NAD(P)H: quinone oxidoreductase in patients with urological malignancies.

The NQO1 locus on chromosome 16q2.2 encodes NAD(P)H:quinone oxidoreductase, an enzyme implicated in detoxication and protection against redox cycling. Two alleles have been identified in the human population, the rarer one, termed the null-allele, coding for a nonfunctional enzyme. Since lack of NQOR activity has been suggested to increase susceptibility to certain cancers, the distribution of the two alleles was determined by polymerase chain reaction-restriction fragment length polymorphism analysis in patients with renal cell carcinoma (n = 131) and urothelial carcinoma (n = 99) compared with a normal population (n = 260). Allele distribution in the normal population followed a Hardy-Weinberg distribution with frequencies of 0.867 for the major allele and 0.133 for the null-allele. Increased frequencies of the null-allele were found in the tumour patient groups (0.191 and 0.182, respectively) due to an increased number of both homo- and heterozygotes. The odds ratios for homozygous null-allele vs. wild-type genotypes were 1.7 and 3.6 for renal cell carcinoma and urothelial carcinoma, respectively. These data are compatible with the assumption that diminished activity of NQOR in some individuals increases susceptibility to certain cancers.

WAF1/p21 regulates proliferation, but does not mediate p53-dependent apoptosis in urothelial carcinoma cell lines.

The WAF1/p21 gene product is an inhibitor of cyclin-dependent kinases which can be induced by the tumor suppressor p53 and mediate some of its effects, or function in p53-independent pathways of cell cycle regulation. Although a potential tumor suppressor gene, WAF1/p21 is expressed in bladder cancer. To elucidate the function of p21 in tumor cells we have investigated in urothelial carcinoma cell lines: i) WAF1/p21 mRNA and protein expression, ii) the biological effects of p21 overexpression or down-regulation and (iii) whether p21 can be induced by p53. WAF1/p21 mRNA levels examined in four cell lines were comparable to bladder mucosa. One cell line, HT1376, failed to express p21 protein due to a frame shift mutation. Overexpression of WAF1/p21 cDNA inhibited clone formation in three cell lines, whereas transfection with antisense WAF1 increased clone sizes and numbers. WAF1 sense clones showed diminished cell proliferation compared to the parental cell line. Apoptosis- induced wild-type p53 was not inhibited by overexpression of antisense WAF1/p21. In a cell clone derived from line VMCub1 by stable transfection with wild-type p53 under the control of a metallothionein promotor, p21 was induced along with p53 upon activation of the promoter with zinc chloride. This induction was accompanied by a decrease in cell proliferation but by little apoptosis. These data suggest that p21 inhibits proliferation in a p53-dependent or independent manner but does not mediate p53-induced apoptosis in urothelial carcinoma cells.

Accuracy of imaging modalities in staging the local extent of prostate cancer.

In this study, none of the evaluated clinical staging methods was found to predict reliably the presence or absence of extracapsular growth of histologically proved carcinoma of the prostate. In this respect, digital rectal examination, transrectal ultrasound, CT, and MR imaging cannot contribute to treatment decisions in localized prostate cancer. Further studies are under way to determine the value of 7.5-MHz scanners in transrectal ultrasound and high-resolution surface coils in MR imaging.

Filter immunocytology: methodologic evaluation of a new assay for the diagnosis of urothelial cancer.

OBJECTIVE: Several investigators have demonstrated the high sensitivity of immunocytology in the diagnosis of transitional cell carcinoma (TCC). A new technique, designated "filter immunocytology" (FLIC), simplifies the technique of quantitative immunocytology, considerable decreases assay time and increases the percentage of assessable specimens. STUDY DESIGN: Voided urine samples were obtained from 89 patients without evidence of TCC and from 91 patients with histologically proven TCC. The cells were transferred onto a polycarbonate membrane. Immunostaining was performed using monoclonal antibody. Due ABC 3, directed against a differentiation antigen on urothelial cells. Specimens containing > 35% positive urothelial cells were regarded as abnormal. RESULTS: Of 153 specimens 180 (85%) were assessable. The investigation of 76 specimens from control patients and 77 from patients with TCC yielded a specificity of 86% and a sensitivity of 75%, respectively. Sensitivity did not correlate with tumor grade. Despite high interobserver and intrapatient variations regarding the amount of antigen-positive cells, a concordant attribution to either "normal" or "abnormal" was made in > 95% of cases. Intraobserver variation was small and did not influence the test result. CONCLUSION: These results suggest that FLIC assay may be a valuable adjunct to conventional cytology. A careful prospective investigation appears to be worthwhile to further define the indications for this technique.

[Indications and follow-up of total pelvic exenteration]. / Indikationsstellung und Verlauf bei der totalen pelvinen Exenteration.

From 1988 to 1996 we performed 18 total pelvic exenterations in patients with an average age of 59.8 years who could be followed up for a mean 29.8 months. In 10 cases a recurrent tumor of the pelvic viscera and 7 times a primary carcinoma of the rectum, bladder or prostate were treated. In 1 patient a radiogenic fistula led to this operation. Intestinal continuity could be reconstructed in 7 cases. Following cystectomy, urinary diversion was accomplished in half of the cases by an ileal conduit. Due to septic multiorgan failure 2 patients died postoperatively (hospital mortality rate 11%). In 82% a complete resection (R0) was possible. Subsequently 5 patients (29%) developed tumor recurrence. Distant metastases were observed in 3 patients, 8-9 months after surgery. So far 10 further patients have died. Their mean survival time was 28.9 months (range 5-99 months). The remaining 6 patients are still alive between 22 and 36 months postoperatively. Despite the extent of this kind of major surgery, which also requires multidisciplinary cooperation, and the psychosocial problems resulting from two permanent stomas, total pelvic exenteration should be regarded as an adequate alternative in the treatment plan in selected patients with locally advanced or recurrent pelvic disease.

[Prognostic factors for predicting the success of immunotherapy in metastatic renal cell carcinoma]. / Prognostiche Faktoren zur Vorhersage des Erfolges einer Immuntherapie beim metastasierten Nierenzellkarzinom.

Only approximately 20% of the patients with metastatic renal cell carcinoma who undergo systemic immunotherapy will respond to this form of treatment. Appropriate selection of patients could exclude many who will not benefit from immunotherapy from a toxic and expensive treatment. Several factors predicting the outcome of immunotherapy have been reported so far. These predictors can be classified into (1) patient-related factors, (2) tumour-related factors and (3) alterations of the immune system during immunotherapy. Performance status and the interval between tumour nephrectomy and metastasization are the most important patient-related factors. Liver metastases are apparently an unfavourable tumour-related prognostic factor. Various alterations of the immune system during immunotherapy are significantly linked with the outcome of the treatment. In consequence, the prospective investigation of prognostic factors within clinical trials appears to be mandatory.

[Immunotherapy of superficial bladder cancer]. / Immuntherapie des oberflächlichen Harnblasenkarzinoms.

Because patients with superficial bladder cancer are in a high-risk group where tumor progression is concerned, topical therapeutic strategies are necessary to prevent tumor recurrence and tumor progression. Based on experimental studies and several case reports, during the last two decades immunotherapy for superficial bladder cancer has been developed. The effects of topical instillation of bacillus Calmette-Guerin (BCG) has been carefully investigated in numerous clinical trials. Especially patients with carcinoma in situ appear to benefit from BCG therapy. Other types of local immunotherapy, e.g., instillation of interferons, interleukins, and keyhole limpet hemocyanin have been found to have fewer side effects than BDG. These new approaches are currently under clinical investigation.

[A study of the quantitative dual-parameter flow cytometry analyses of cellular antigens on transitional cells for the diagnosis of bladder cancer].

To establish a quantitative dual-parameter flow cytometry (FCM) analysis of cell surface antigens, possible obstacles caused by contaminated leucocytes in a specimen and staining and measuring conditions were investigated using human bladder cancer cell lines, 5637, T24 and SW1710. The first monoclonal antibody (MoAb) used to select urothelial cells in a specimen was applied with the second MoAb used to discriminate between normal and transformed urothelial cells. MoAbs Due AUT 2 and CD45 appeared to be suitable for the selection of urothelial cells, while Due ABC 3 and Due ABC 5 were applied to detect transformed cells. Tumor cell-leucocyte suspension was simultaneously stained with combinations of these MoAbs. The results demonstrated that Due AUT 2 and CD45 effectively eliminated contaminated leucocytes by means of positive and negative selection of the urothelial cells, respectively. Based on these experiments, dual-parameter FCM analyses of bladder washing from 5 patients with bladder cancer were performed using MoAbs Due AUT 2 and Due ABC 3. The results indicated that by dual-parameter FCM distinct antigenic features of transitional cells could be investigated even if considerable amounts of contaminated leucocytes were present. The clinical impact of this approach is a subject of ongoing trials.

[Nutritional prevention of urological tumours]. / Alimentäre Prävention urologischer Tumoren.

Through the last decade considerations on the role of vitamins and antioxidants in the primary prevention of genitourinary tumors have changed dramatically. In spite of all efforts, the efficacy of a specific compound has not been proven so far. In consequence, recommendations to use vitamins or other supplements for the primary prevention of urological tumors should be avoided. However, there is some evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet may not only prevent prostate cancer (PCA) but also harbour additional beneficial effects on general health. Although quantification of these findings may be difficult, it becomes evident that these measures will have additional synergistic effects on cardiovascular diseases. Considering the large number of PCA patients dying not cancer-related but from concomitant diseases, primary prevention in particular of PCA should always also consider the general health of the target population. More recent studies suggest a potential effect of nutritional compounds on biochemical tumour recurrence in PCA patients after definite therapy. These observations may serve as a starting point for validation within controlled clinical trials.

[Metabolic syndrome and prostate cancer]. / Metabolisches Syndrom und Prostatakarzinom.

The relationship between metabolic syndrome (MS) and prostate cancer (PCA) is highly complex and harbors multiple facets not least because MS is not a single entity but represents a poorly defined inhomogeneous mixture of different diseases and conditions. Although numerous studies suggest a correlation between MS or components of MS and the development of prostate cancer, current evidence cannot be considered convincing. While diabetes appears to be inversely related to PCA, increased serum levels of triglycerides, cholesterol and insulin-like growth factor 1 (IGF-1) may be predictive for high grade disease. Further studies suggested that MS and high serum insulin levels are independent predictors of an unfavorable prognosis in patients with metastatic PCA. Early detection and improved therapeutic options have dramatically prolonged the course of the disease in advanced PCA through the last decades. As a consequence, development of MS in patients undergoing hormone therapy along with the cardiovascular risks has gained increasing relevance. Based on this evolution prevention, early detection and sustainable therapy represent an important clinical challenge to modern urologists active in urooncology.

[What can medicine expect from health economics?]. / Was erwartet die Medizin von der Gesundheitsökonomie?

Medicine has changed dramatically in the past ten decades thanks to the introduction of innovative diagnostic and therapeutic procedures. However, besides the unmistakable advances achieved in medicine, the costs of all health care systems have risen dramatically. In contrast to the escalation in expenditures, only moderate gains in proceeds have been accomplished. This situation requires that future financial resources be judiciously expended. The field of health economics has set as its goal the analysis of medical measures in terms of costs and benefits to be able to provide information on these parameters to those involved in the public health sector. The emerging problems are diverse and extend from assessment of effects and side effects to difficulties in standardizing analytical procedures and comparing results between different health care systems.In the context of this manuscript an attempt has been made to illustrate the methodological approaches to health economics based on current issues in the diagnosis and treatment of prostate cancer. This contribution intends to motivate stakeholders to view health economics as a tool to promote improvements in medical care and not as a means to regulating and rationing medical measures.

[Chemoprevention of prostate cancer - a plea]. / Chemoprävention des Prostatakarzinoms - Ein Plädoyer.

The high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make the diagnosis of and therapy for prostate cancer a special challenge for urologists. Effective prevention of the disease may help to improve some of the problems mentioned above. Two randomised, controlled studies have proved that effective chemoprevention of prostate cancer is viable using 5α-reductase inhibitors (finasteride, dutasteride). Furthermore, there is increasing evidence that other compounds, e. g., selective oestrogen receptor modulators (SERMs), NSAIDs and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economical aspects. The authors conclude that the options of chemoprevention should be investigated in an open and unbiased way.

[Supportive options in the treatment of urological tumours]. / Supportion in der urologischen Tumortherapie.

An ageing society with a consecutive increase of genitourinary malignancies along with remarkable changes in systemic cancer therapy provide the basis for an increasing role of supportive measures. While surgical treatment, radiation or chemotherapy are undergoing subsequent standardisation, supportive measures are still widely used on the basis of personal experience alone. However, effective support is the prerequisite for a successful systemic treatment. Within this review the most relevant side effects of systemic therapy for urological tumors are summarised and the respective therapeutic options are presented in a brief but practice-oriented way. The authors have aimed at the consideration of evidence-based measures, wherever possible.