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.

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.

Imaging prostate cancer with technetium-99m-7E11-C5.3 (CYT-351).

UNLABELLED: To evaluate the performance of the 99mTc-labeled monoclonal antibody CYT-351 in visualizing prostate cancer, radioimmunoscintigraphy (RIS) was performed in 35 patients. METHODS: Antibody (0.5 mg) labeled with 600 MBq 99mTc was injected intravenously after obtaining informed consent. Planar and SPECT imaging was performed at 10 min and 6-8 and 22-24 hr postinjection. The scans were evaluated for visualization of the primary focus or local recurrence, extraprostatic invasion, lymph node involvement and uptake in bone and soft tissue metastases. RESULTS: Thirty-six studies in 35 patients were performed. In 13/14 evaluable studies with clinically localized prostate cancer, RIS had a true-positive rate of 92% (12/13). In eight patients with previous incidental carcinoma detected during transurethral resection undertaken for clinically benign disease, there were 86% true-positive results (6/7) and one true-negative result, which were confirmed by systematic needle biopsies. In six patients with evidence of local recurrence after a previous radical prostatectomy, the true-positive rate was 100% (6/6), which was confirmed by raised or rising prostate-specific antigen levels (PSA) and/or by biopsy. In the eight patients with known metastases, the disease was visualized in 4/4 with progression but not in the 3/3 with regression; one patient demonstrated regressing disease as determined by PSA levels. The overall accuracy was 92%. CONCLUSION: RIS with 99mTc CYT-351 is capable of providing good quality images and yielding clinically useful information safely. It has a potentially important clinical role for patients with rising PSA levels but negative images by conventional modalities.

Villous composition and membrane thickness in the human placenta at term: a stereological study using unbiased estimators and optimal fixation techniques.

The aim of this study was to obtain unbiased estimates of in vivo villous composition and membrane thickness in the human placenta at term. By taking biopsies of the placenta 1 min after separation during caesarean section, and at regular intervals thereafter, it was possible to extrapolate back to the time zero values. It was estimated that at term intermediate and terminal villi are composed of 25.3 per cent trophoblast, 36.2 per cent stromal core and 37.1 per cent fetal capillaries. The villous membrane, defined as the outer surface of the syncytiotrophoblast (excluding the microvilli) to the inner surface of the capillary endothelium, was estimated to have an arithmetic mean thickness of 4.53 microns and a harmonic mean thickness of 3.65 microns. Villous composition and membrane thickness were found to change rapidly after delivery, despite the umbilical cord remaining clamped, and these changes were believed to be predominantly due to leakage of fetal blood or plasma from sites of damage to the villous tree caused at the time of delivery. These estimates do not, and indeed cannot, take into account the fact that the villi sampled have been removed from their uterine environment, and thus from the influences of the maternal and fetal blood pressures. However, they are free from methodological errors that have detracted from previous studies, and thus allow the morphometric diffusing capacity of the placenta at term to be calculated more accurately. They also provide baseline data against which measurements obtained from pathological pregnancies can be compared.

Ki-67 expression in early prostate cancer and associated pathological lesions.

AIM: To assess cell proliferation in early prostate cancer and associated pathological lesions. METHODS: Using the Ki-67 antibody, the cell proliferation index was measured in early stage prostatic carcinoma in 37 incidental tumours diagnosed at transurethral prostatectomy (TURP) and in 20 low volume cancers treated by radical prostatectomy. Proliferation indexes have also been measured in areas of normal peripheral zone, transition zone hyperplasia, atrophic appearing lobules, and high grade prostatic intraepithelial neoplasia in the radical prostatectomy cases. RESULTS: In the TURP series the proliferation index correlated with grade and stage. Logistic regression analysis, however, showed that Gleason grade was the most reliable predictor of biopsy proven residual disease and clinical progression. In the radical series transition zone carcinoma the proliferation index was half that of peripheral zone carcinoma. The atrophic lobules also showed a high proliferation index of the same order as seen in the peripheral zone carcinoma. Normal peripheral zone showed the lowest proliferation index and in hyperplastic transition zone it was also less than the other areas. CONCLUSIONS: There is only limited support for the correlation of proliferation index with grade in early stage prostatic carcinoma. The findings do not suggest that proliferation index adds to the prognostic information given by grade and stage in pT1 disease. The significant difference in proliferation index in transition zone and peripheral zone carcinomas supports the morphological distinction of these tumour types and is consistent with differences in biological behaviour. The high proliferation index in lobules considered morphologically atrophic is reminiscent of previous observations in which carcinoma was spatially associated with atrophy.

Reproducibility of uroflow measurement: experience during a double-blind, placebo-controlled study of doxazosin in benign prostatic hyperplasia.

OBJECTIVES: To evaluate the interindividual and intraindividual variation of uroflow measurements in men with benign prostatic hyperplasia (BPH). METHODS: A total of 147 men with clinical evidence of BPH underwent two uroflow measurements at each of two screening visits prior to recruitment into a placebo-controlled study of doxazosin in the treatment of BPH. The maximum and mean flow rates were determined on each occasion. Differences in the mean value of both parameters for the cohort were examined. The intraindividual variability was evaluated using intraclass correlation coefficients and differences in maximum uroflow at each visit were examined. RESULTS: Uroflow measurements for the cohort were reproducible and there was no clinically significant difference in maximum and mean flow rate on each occasion. However, the intraclass correlation coefficients for the mean and maximum flow rate varied between 0.70 and 0.82, indicating that intraindividual variation accounted for a substantial component of the total variation in uroflow observed among these patients. For many individuals, test-retest differences were clinically relevant. CONCLUSIONS: For a group of patients, maximum and mean uroflow measurements are reproducible. However, for an individual, these parameters are subject to clinically significant variation and a single measurement may not be representative. This may be important when considering the need for therapeutic intervention.

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.

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.

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.

Acute bilateral vestibulo-cochlear dysfunction following occipital fracture.

The case of a 57-year-old man who presented with acute bilateral deafness and vestibular dysfunction following occipital bone fracture is described. Plain radiographs and a CT scan of the head demonstrated a single fracture of the occipital bone. Complete loss of cochlear and vestibular function bilaterally was demonstrated and followed by partial recovery of auditory function over the following months. Review of the literature has not revealed a previously reported case.

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.

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.

The contribution of research to urological training in the United Kingdom.

OBJECTIVES: To report the findings of a questionnaire survey among consultant urologists in the United Kingdom (UK) designed to examine their personal experience of research and their opinion of its contribution in urological training. METHODS: A questionnaire was sent to 205 consultant urologists in the UK and 154 (75%) replied. Their replies were examined to ascertain the time spent in research, the production of publications, presentations and in gaining a higher university degree. Subsequent research activity was also related to the achievement of these endpoints. RESULTS: Among the 154 consultant urologists who replied. 130 (84%) had undertaken research during their training, for a period varying from 6 months to more than 2 years. Among the 130, 99 (76%) considered this to have been well spent; 76 (58%) obtained a higher degree, 86 (66%) achieved at least three publications in peer-reviewed journals and 90 (69%) had given at least five presentations to learned societies. Inadequate supervision in particular was cited as contributing to underachievement and motivation was also considered important to success. CONCLUSIONS: The contribution of research in urological training has been assessed traditionally by the presentation of a thesis to a university for a higher degree, but alternative methods of assessment should perhaps be sought for those wishing to spend less than 18 months in research.

Capillary volume fraction is the principal determinant of villous membrane thickness in the normal human placenta at term.

The thickness of the villous membrane is known to be an important factor in determining the morphometric diffusing capacity of the placenta at term. As yet it is not certain how areas of the villous membrane specialised for gaseous exchange, the vasculo-syncytial membranes, differentiate. One mechanism suggested is that they arise through obtrusion of the fetal capillaries contained within the stromal core. As a result the bulk of the overlying trophoblast is displaced laterally, reducing the thickness of the villous membrane to as little as 1-2 microns at these points. To test this hypothesis the relationship between the vascularity of the villi, as determined by the villous capillary volume fraction, and the mean thickness of the villous membrane was investigated. Data were taken from a recent study in which placental villi were biopsied from normal term placentae within 1 min of caesarean delivery and at 5, 10, 15 and 20 min thereafter. Since intuitively the membrane has both a maximum and a minimum thickness a sigmoid relationship was fitted to the data using least squares regression analysis. Estimates of arithmetic and harmonic mean thicknesses were then predicted from the capillary volume fraction for a large number of placentae using data from previous studies. These all employed similar stereological techniques but were performed over a number of years by several workers in this laboratory. The predicted values were tested against the measured values using paired 't' tests, but no significant differences (P greater than 0.05) were detected.(ABSTRACT TRUNCATED AT 250 WORDS)