Management of oncological and iatrogenic urinary incontinence in malignant disease.

Urinary incontinence can have a major effect on quality of life, and may contribute to overall disability in patients with abdominal and pelvic malignancy. It can lead to isolation and depression, and delay rehabilitation and integration within family and society. With prompt assessment and correct management, urinary leakage can be controlled and many of the problems associated with urinary incontinence can be prevented to the patient's satisfaction. In oncological patients, this is best achieved in a multidisciplinary approach. This involves close co-operation between the oncologist, urologist, specialist nurses and individual patient, setting realistic expectations, guided by the patient's views and wishes. This paper reviews the management of urinary incontinence and its surgical treatment in the palliative setting.

Palliation of male genital cancers.

Advanced genital tumours are rare. Traditionally, surgical intervention in these patients has had a limited role due to the associated co-morbidities, poor performance status and overall poor prognosis. Because the potential benefit of surgical intervention in advanced cases is not evidence based, a large proportion of these patients are treated palliatively with chemoradiation therapy, which may have a limited role in advanced disease together with no significant improvement in quality of life for the patient. We present a review of palliative surgical techniques and non-surgical interventions in a range of male genital malignancies. Although the focus relates to advanced tumours with a palliative intent, a brief discussion on treatment with a view to cure is also covered. The traditional dogma is challenged with demonstration of value in surgery as part of multimodal therapy. Various surgical techniques that are used not only to excise the primary tumour, but also those of reconstruction of the urinary tract as well as techniques of flap and graft-based coverage are described. We show the essential role of surgery as part of multimodal therapy in well-motivated patients. No longer is surgery considered as having a limited role in these patients with advanced male genital malignancy.

Pelvic exenterative surgery for palliation of malignant disease in the robotic era.

A Medline-based literature review was carried out of the surgical management of advanced pelvic cancers and the effect of minimally invasive technology in this setting to review the current status of exenterative surgery for advanced pelvic malignancies. Palliation and/or resection of advanced pelvic cancer affecting one or more pelvic compartments offers benefit and improved quality of life in carefully selected patients. This complex surgery is best carried out by experienced multidisciplinary teams after meticulous preoperative staging and assessment. Survival rates at 5 years are between 25 and 40% in the absence of metastatic disease and between 18 and 24 months in the palliative setting. Open surgery remains the gold standard approach, but emerging reports of laparoscopic and robotically assisted laparoscopic techniques may be feasible in highly selected individuals.

PSA testing: an evolving relationship with prostate cancer screening.

PSA testing has made prostate cancer screening a reality for men in many parts of the world, but its benefit for men's health continues to be debated. In men exposed to PSA testing, there has been a well-documented change in the presentation of prostate cancer with a shift towards earlier pathological stage, not without justifiable concern about over-diagnosis by prostate biopsy. Increasingly, men now diagnosed with early stage cancer have previous PSA exposure and are selected for biopsy based on PSA change in relation to cutoff values. Some recent observations suggest that PSA may no longer be an effective marker for early stage tumours, with PSA elevation failing to discriminate tumour-specific characteristics from benign gland enlargement. Traditionally, variation in pathological stage of clinically localised prostate cancer at diagnosis has related to clinical stage, PSA and biopsy Gleason grade, but with distinctions based upon these three assessments declining and an increasing proportion of organ-confined tumours at presentation, new methods of cancer detection and prognostic assessment are now required. Molecular technologies hold great promise in this respect, and in the future biomarker signatures are likely to overshadow total PSA for guiding early diagnosis and prognostic assessment. While arguments about prostate screening will continue, owing not least to its feasibility, future debate is likely to focus increasingly on technological advances and molecular profiling of these notoriously heterogeneous tumours.

Genome-wide screening for genetic changes in a matched pair of benign and prostate cancer cell lines using array CGH.

Copy number alterations in a matched pair of benign epithelial and prostate cancer cell lines derived from the same patient were assessed using array-based comparative genomic hybridisation (aCGH). The cancer cell line showed a gain of chromosome 7, deletion of chromosome 8, gains (including high level) and losses on chromosome 11, loss of 18p and gain of 20q. Deletions on chromosome 8 were confirmed with microsatellite markers. The aCGH results were compared to gene expression data obtained using DNA microarrays and suggested the involvement of caspases and ICEBERG on 11q and E2F1 on chromosome 20q.

Indicators of pathologic stage of prostate cancer and their use in clinical practice.

Pathologic stage is the most reliable means of predicting the likelihood of curable prostate cancer at the time of definitive treatment. Its prediction is of the greatest importance to individuals with clinically localized disease, principally because of the therapeutic and prognostic implications. Multivariate models integrating variables that can be derived from clinical and pathologic assessment have been shown to be reliable and useful in urologic practice. Among these variables, the combination of clinical stage, serum PSA, and biopsy Gleason score provides reliable assessment of the risk for extraprostatic disease that can be used readily for counseling individual patients. Other biopsy-derived parameters may contribute additional information, but their value in multivariate analysis has not been validated in a multi-institutional setting. The development of new prognostic markers is a priority objective in current research to distinguish patients in whom cancer cannot be controlled by surgical treatment. For patients undergoing radical prostatectomy, definitive pathologic stage certainly will remain an important prognostic factor; therefore, clinical practice will continue to be determined by its accurate prediction.

Transduction and apoptosis induction in the rat prostate, using adenovirus vectors.

Proapoptotic adenovirus vectors offer great promise for the treatment of cancer and nonmalignant conditions. Benign prostate hyperplasia (BPH) is a common nonmalignant enlargement of the prostate that involves epithelial, stromal, and smooth muscle components of the gland. We tested the hypothesis that an adenovirus vector expressing Fas ligand can be used to induce apoptosis in the prostate. We analyzed the efficiency of transduction and apoptosis induction in primary cultures of human prostate cells after adenovirus-mediated gene transfer. Efficient transduction was observed in primary prostate epithelial cells. Stromal and smooth muscle cells were more difficult to transduce, as no coxsackie-adenovirus receptor (CAR) expression was detectable on these cells. However, transduction was achieved in these cells when the multiplicity of infection was increased to 100 focal-forming units per cell, or when the vectors were delivered as calcium phosphate precipitates. Infection of all three primary prostate cell types with an adenovirus vector that expresses Fas ligand (AdFasL/G) resulted in rapid apoptosis. Direct injection of the rat prostate with an adenovirus vector carrying luciferase resulted in substantial luciferase expression. TUNEL analysis demonstrated that AdFasL/G administration induced low-level apoptosis in prostatic epithelial cells throughout the gland. As a first step toward enhancing the efficiency of prostate transduction in vivo, we tested an adenovirus vector that was engineered to have an expanded tropism. This vector, AdZ.F2K(pK7), was 10- to 500-fold more efficient than unmodified vectors in transducing prostate epithelial, smooth muscle, and stromal cells in culture. Moreover, AdZ.F2K(pK7) was more efficient than an unmodified vector at transducing the rat prostate in vivo, although the effect was dose dependent.

Management dilemmas in bladder cancer: radical TUR +/- systemic chemotherapy in the treatment of muscle-invasive bladder cancer.

This case report follows the course of a highly aggressive bladder cancer that presented with carcinoma in situ and illustrates the rapid rate of progression from superficial to invasive disease that may be observed in some individuals. This case also highlights concerns about alternative management options and the dilemmas that arise when cystectomy is delayed by failed conservative strategies attempting to preserve the native bladder. This discussion focuses on the combination of radical transurethral resection (TUR) and systemic chemotherapy as a therapeutic alternative to cystectomy. The concept, technique, indications, and contraindications of radical TUR, and the rationale for combination systemic chemotherapy are discussed with reference to this case. We consider the value of radical TUR and systemic chemotherapy as an alternative to cystectomy and the reasons why this patient would not have been a suitable candidate for this bladder-sparing approach.

Today men with prostate cancer have larger prostates.

OBJECTIVES: To examine the relationship between prostate size and the method of cancer detection in men with organ-confined prostate cancer, and compare prostate size in men with and without cancer. METHODS: Prostate volume was evaluated in 720 men who had undergone radical prostatectomy for Stage T1c or Stage T2 cancer. Men with Stage T2 cancer were divided into those treated before 1989 (when widespread prostate-specific antigen [PSA] testing began), or not. Gland volume was also examined in 265 men participating in the Baltimore Longitudinal Study of Aging who had no clinical evidence of cancer. Volumes were compared using linear regression to allow for age. RESULTS: Prostate volume in men with Stage T1c cancer was statistically significantly larger than in men with Stage T2 cancer diagnosed in the pre-PSA era after adjusting for age (P = 0.0001), and statistically significantly larger than in men without cancer above age 47 years based on 95% confidence intervals. Prostate volumes in men with Stage T2 cancer diagnosed in the pre-PSA era and in men without cancer were not statistically significantly different. CONCLUSIONS: Prostate volume in men with PSA-detected, organ-confined cancer is larger than in men with palpable organ-confined cancer diagnosed in either the pre-PSA era or PSA era. These discrepancies may reflect a diagnostic bias due to the effect of benign prostatic hyperplasia on serum PSA that results in the selection of men with larger prostates for biopsy.

Diagnosis of localized prostate cancer: 10 years of progress.

Advances in the diagnosis of early stage disease, and particularly the introduction of prostate-specific antigen (PSA) testing, have had a dramatic effect on the presentation and clinical management of prostate cancer during the past ten years. As a result, there have been significant epidemiological changes in countries where early diagnosis is recommended. The importance of PSA testing for the diagnosis of localized prostate cancer has become well established in clinical practice and this is reflected by improved outcomes from definitive treatment. The contribution of PSA-related parameters and molecular forms of PSA both to cancer detection and prediction of pathological stage continue to be explored. Concerns about the reliability of the standard sextant biopsy technique for cancer detection relate to the need for re-biopsy in a growing number of patients with negative biopsies and an increasing proportion of patients with low volume, multifocal disease. In men with cancer, additional prognostic information can be derived from biopsy findings, with important therapeutic implications. This relates also to the need for reliable markers indicating pathological stage and risk of progression. The opportunities for the prevention of prostate cancer have grown with improved understanding of its biology and the genetic basis of the early steps associated with malignant transformation. In the future, the need for therapeutic intervention is likely to be most influenced by successful prevention strategies.

Imaging with prostate-specific membrane antigen (PSMA) in prostate cancer.

Radioimmunoscintigraphy using a radio-labelled antibody to prostate-specific membrane antigen (PSMA) has growing applications as a means of tissue-specific imaging based on functional characteristics and complements traditional staging investigations. Clinical applications in men with carcinoma of the prostate are being refined, and this study reports outcomes with this technique in our practice. Prostatic immunoscintigraphy scans were performed with In-111 CYT 356 in 49 men with carcinoma of the prostate, obtaining sequential images in two and three dimensions at 10 min, 24 and 48 h. Of the 49 men, 36 had clinically localized cancer, 10 had recurrent disease after radical radiotherapy or radical prostatectomy and three had rising PSA after primary endocrine treatment. Scan findings are discussed in the context of clinical management. Of the 36 men with clinically localized cancer, seven had increased uptake in regional and distant lymph nodes. Of these seven, three were treated with hormone manipulation, two by radical prostatectomy and two by radical radiotherapy. Among 10 patients who had recurrence after radical treatment of the primary tumour, scans showed local recurrence alone in four, and six had regional or distant metastases. Three patients treated with primary hormone manipulation had scans for rising PSA, and of these one had a positive regional node and two had distant soft tissue and bone metastases. In conclusion, prostatic radio-immunoscintigraphy scans highlight tissues involved by prostate cancer, including the prostate, lymph nodes, soft tissues and bone metastases as well as pelvic recurrence. Results may contribute to the clinical management of individual patients, although histological confirmation may be appropriate when considering alternative treatment. Prostate Cancer and Prostatic Diseases (2000) 3, 47-52

Funding clinical research: the need for information and longer term strategies.

The Chief Medical Officer's Working Group on Specialist Medical Training recommended that training in research methodology should be a recognised component of all postgraduate training programmes and that further consideration be given by those responsible for postgraduate education, training and research to establishing how this might be achieved. Funding of the trainee in research is a crucial aspect of this directive, yet both trainers and trainees have described this as haphazard, invariably reliant on 'soft' money. The subject has raised wide discussion and debate. A questionnaire was sent to 205 consultant urologists in the UK, 154 (75%) replied and 130 (84%) had experience of research during their training. The first report examined their opinion about the contribution of research to their training; this report covers the questions directed towards funding, the source of their funding, whether sufficient funds, advice and information were available and where they might expect to obtain such details. The replies indicated a variety of sources of funding; knowledge about the financial support available for research was sparse and the majority considered there was insufficient advice and information available for trainees on the subject. Substantial funds are available for high quality scientific research programmes providing unprecedented opportunities for multidisciplinary collaboration that is essential for advancing clinical practice alongside technological developments. The process of obtaining support can be a time-consuming exercise, raising the need for an administrative infrastructure to select, prioritise and co-ordinate an appropriate research strategy for the future.

Does screening for prostate cancer identify clinically important disease?

In this study the combination of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) is shown to be effective for detecting early prostate cancer in a urological out-patient setting. PSA provides the means to detect cancer in men with normal DRE that may otherwise present as so-called incidental cancer at transurethral resection of the prostate (TURP) for apparently benign disease or later in the course of its natural history as locally advanced or metastatic disease. PSA progression in men with incidental cancer has been previously demonstrated to be predicted more reliably by residual cancer on needle biopsy after TURP than by tumour in the resected specimen and, therefore re-staging such patients is worthwhile when further treatment would be considered. Among men selected for radical prostatectomy, non-palpable tumours detected with PSA more predictable in pathological extent than incidental cancer and their particular pathological characteristics suggest they include clinically significant tumours that would progress if untreated to palpable and eventually metastatic disease. In view of this progressive behaviour, cancer detected by PSA should be considered clinically significant particularly in men with a life expectancy of at least 10 years. Therefore screening should be offered for such individuals, to detect and treat tumours at a curable stage and thereby eliminate the high mortality and often protracted morbidity commonly associated with metastatic disease.

Selectivity of finasteride as an in vivo inhibitor of 5alpha-reductase isozyme enzymatic activity in the human prostate.

The type II 5alpha-reductase inhibitor finasteride is used in the treatment of benign prostatic hyperplasia (BPH), reducing local production of the growth promoting androgen dihydrotestosterone (DHT). The effect of prolonged treatment with this time-dependent irreversible inhibitor on the recently described prostatic type I 5alpha-reductase, however, is not clear. Therefore, we assessed the effects of 5 mg. finasteride per day for 6 months on prostatic 5alpha-reductase isozymes, and prostatic tissue composition and androgen content of patients suffering from BPH. In prostatic tissue from these patients, the type II enzymatic activity is inhibited 100-fold compared with tissues obtained from placebo treated patients. The type II immunoreactivity is up regulated 2-fold. The type I isozyme is inhibited 3-fold and potentially still contributes to DHT production. In conclusion, finasteride is a selective type II inhibitor in vivo. Further research is warranted to assess the possibly distinct roles of the 5alpha-reductase isozymes in the normal prostate, in BPH, and during finasteride treatment.