Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

A novel coculture model for benign prostatic hyperplasia expressing both isoforms of 5 alpha-reductase.

We have developed a coculture system for primary fibroblast and epithelial cells derived from benign prostatic hyperplasia (BPH) that retained many of the characteristics of the intact human prostate. In contrast to separately cultured prostate fibroblast and epithelial cells, cocultures of fibroblasts and epithelial cells maintained messenger ribonucleic acid expression and functional activity for both isoenzymes of 5 alpha-reductase (type I and type II) as well as maintained expression of androgen receptors and prostate-specific antigen. Furthermore, levels of prostate-specific antigen secreted by cocultured epithelial cells were increased by treatment with androgens, mimicking the situation in the human gland. This contrasted with conventionally cultured fibroblasts or epithelial cells, which failed to express 50 alpha-reductase type II and rapidly lost expression of androgen receptors and androgen sensitivity upon being placed into culture. Electron microscopy demonstrated intracellular structures indicative of the differentiated state of the cocultured cell types, including round nuclei, tonofibrils, and microvilli in epithelial cells and elongated nuclei; large amounts of Golgi and cilia; along with immature collagen fibers in fibroblasts. The present study demonstrates that the coculture model reflects more closely the in vivo system for human BPH and is thus a far more suitable model for investigating the molecular and cellular events that underlie BPH than current in vitro systems.

The localisation and expression of 5 alpha-reductase types I and II mRNAs in human hyperplastic prostate and in prostate primary cultures.

The expression and localisation of mRNAs for 5 alpha reductase Type I (5 alpha R-I) and Type II (5 alpha R-II) isoenzymes in human benign prostatic hyperplasia (BPH) were investigated by RT-PCR and by in mini hybridisation (ISH) using digoxigenin labelled riboprobes. In addition, we also examined the isoenzymes mRNA expression in primary BPH cultures of separated stroma/fibroblast and epithelial cells to determine whether primary cultures are appropriate models in which to investigate 5 alpha R activity and regulation. The results demonstrated conclusively the presence of mRNA encoding both isoenzymes in all specimens so far examined. Additionally, the presence of a functional 5 alpha R-I and -II activity in BPH was confirmed by enzyme assays. ISH studies localised the mRNA expression to both the fibroblast/stromal component as well as the epithelial cells of the hyperplastic tissue. In the glandular regions the expression for both isoenzymes was particularly strong in the basal layers of the epithelium whereas mRNA expression in the secretory cells was less pronounced. Expression of 5 alpha R-I and -II mRNAs in fibroblast was on the other hand variable with high expression in some areas and little in others. These findings were supported by our primary culture experiments which demonstrated that both the fibroblast and epithelial cells maintain a capacity to express both isoenzymes in vitro. In the case of the fibroblast, the capacity to express the isoenzymes was maintained following the sequential passaging of the cells up to passage 6, after which the cells no longer expressed either isoenzyme.

Differential production of gamma delta T cells in the urine of bladder cancer patients receiving Bacillus Calmette Guerin immunotherapy.

Bacillus Calmette Guerin (BCG) intravesical therapy of bladder cancer is arguably the most effective immunotherapy for any human solid tumour. It combines a high incidence of remission induction with a low level of side effects and a low rate of recurrence. Its mechanism, however, remains poorly understood. In this study we have investigated whether gamma delta T lymphocytes, which are known to be activated by mycobacteria, are preferentially induced in patients urine following therapy. This has necessitated the development of a procedure which facilitates the preservation, enrichment and detection of small number of lymphocytes [especially of those bearing gamma delta T cell receptor (TCR)I which appear in patients urine. Here we describe in detail a method for phenotyping of a minor subpopulation of lymphocytes in patients' urine, namely, gamma delta T lymphocytes which comprised less than 0.1% of all urinary sells. Using this technique we have found gamma delta T cells in the urine of all patients. Furthermore, the patients could be separated into 2 distinct groups, with low and high numbers of gamma delta cells (0.5-5% and 5-20% respectively of the CD3 positive cells). The elevation of gamma delta T cells was observed locally but not in peripheral blood and the detected gamma delta T were almost entirely of the V delta 2 gamma 9 subset.

Radical radiotherapy and salvage cystectomy as the primary management of transitional cell carcinoma of the bladder. Results following the introduction of a CT planning technique.

The objective of this study was to review the results of our policy of primary radiotherapy (RT) and salvage cystectomy for transitional carcinoma (TCC) of the bladder in the light of changes in our radiotherapy planning procedure, in particular the introduction of CT planning. The case notes of 163 patients treated with radical radiotherapy using a CT planning technique were examined. The main endpoint for assessment was response at the time of the check cystoscopy 6 months after the completion of treatment. In addition survival was estimated by stage of disease and by response at the time of first cystoscopy. Patterns of relapse and time to relapse were analysed. All percentages quoted in the text use the initial 163 patients as the denominator. One hundred patients (61%) achieved a complete response. The complete response rate was significantly related to T stage at presentation being 90% for T1, 75% for T2, and 53% for T3 disease respectively. Of these patients 78 remain disease free in the bladder (47%). Twenty-two have relapsed in the bladder, of whom 5 have also relapsed at metastatic sites. Fifteen patients have relapsed outside the bladder whilst remaining disease free within the bladder. At the time of last follow up or death from other causes 63 of the 100 patients who had a complete response remained disease free with an intact bladder. There were 18 (11%) partial responders. Seven of these patients went on to have a cystectomy. Ten remain alive, 7 disease free, 4 with intact bladders. In 24 patients (15%) there was no response and these patients have all died, the median survival being 10 months. In 21 patients (13%) a postradiotherapy cystoscopy was not performed. In all but one patient, who was lost to follow up, this was because of progressive disease. The median survival of these 20 patients was 6 months. Of the 163 patients 35% are alive and well with an intact bladder. If patients dying from other causes are included then 42% were rendered disease free. Cause specific survival was significantly related to stage of disease at presentation with 5 year actuarial survival being 87%, 48% and 26%, for T1, T2 and T3 disease respectively. Survival was also related to response to treatment at 6 months with 5 year survival being 64%, and 52% for complete and partial responders respectively. Survival was extremely poor for non-responders with only 37.5% surviving 1 year and none 5 years. There was a highly significant relationship between response and the development of, and the time to developing metastatic disease. Of those who exhibited a response 21% developed metastatic disease compared to 78% of non-responders. Salvage cystectomy offers the possibility of cure in those who achieve a complete or partial response with 42% of such patients being rendered disease free. Results however are poor in those who did not respond with all patients dying of their disease. Response rates for all stages, and survival for stages T1 and T2 are much improved from those previously reported from this centre and compare favourably with other published series. These results confirm the place of radiotherapy and salvage cystectomy in the management of TCC of the bladder in selected patients. In about one-third of patients the desired outcome of curing the patient of their cancer with organ preservation is achieved. The prognostic significance of cystoscopic response at 6 months and stage at presentation is confirmed. The outcome for patients with early stage disease is excellent. The relationship between response and the development of metastatic disease would suggest that even if these patients had had a primary cystectomy they may have fared badly, a conclusion supported by the fact that these results are comparable with surgical series. This series supports the role of radiotherapy in the management of this disease and suggests that modern RT techniques including CT planning have had a beneficial effect on the results of radical radiotherapy.

Selective interactions between prostate fibroblast and epithelial cells in co-culture maintain the BPH phenotype.

Paracrine interactions between primary cultured prostate epithelial cells and stromal fibroblasts were investigated in relation to morphology, growth, androgen sensitivity and secretory activities using co-cultures in which the two populations were separated by a microporous membrane. In this new model system, both cell types maintained several aspects of the differentiated phenotype including the capacity to express 5alpha-reductase iso-enzymes and androgen receptors, to respond to androgens and to secrete prostate-specific antigen by the epithelial cells. Morphological studies demonstrated that the cells grown in co-culture exhibited round nuclei, tonofibrils and microvilli in epithelial cells and elongated nuclei, large amounts of Golgi apparatus and cilia in the fibroblasts, all indicative of the differentiated state. The co-culture system highlights the importance of the metabolic co-operation between prostate fibroblast and epithelial cells for preserving the phenotypic characteristics associated with the human prostate in vivo.