Paul D. Abel

Cytoplasmic induction and over‐expression of cyclooxygenase‐2 in human prostate cancer: implications for prevention and treatment

Objective To assess the level and morphological distribution of cyclooxygenase (COX)‐1 and ‐2 in human prostates and to determine any association with the Gleason grade of prostate cancer.

Impact of surgery for stress incontinence on morbidity: cohort study.

Abstract Objectives: To describe the impact of surgery for stress incontinence on the severity of symptoms, other mental and physical symptoms, and overall health. To describe the incidence of postoperative complications. Design: Prospective cohort study; questionnaires completed by patients before and 3, 6, and 12 months after surgery. Questionnaires completed by surgeons both before and after surgery. Setting: 18 hospitals in the North Thames region. Subjects: 442 women treated surgically for stress incontinence between January 1993 and June 1994. 367 women returned the 3 month questionnaire; 364 returned the 6 month questionnaire; and 359 returned the 12 month questionnaire. 49 surgeons provided perioperative information on 285 of the 442 women and postoperative information on 278. Main outcome measures: Stress incontinence symptom severity index, other urinary symptoms, bowel function, mental health, complications, global measures. Results: Most women (288; 87%) reported an improvement in the severity of their stress incontinence, though only 92 (28%) were cured (continent). These improvements persisted for at least 12 months. The likelihood of improvement was similar regardless of whether urodynamic pressure studies had been conducted before surgery. Following surgery, women were less likely to suffer from urinary frequency, nocturia, postvoid fullness, dysuria, and urgency. While mental health improved for 194 (71%), a quarter of women reported deterioration. Only 37 (10%) were satisfied with postoperative pain control. A third experienced one or more complications while in hospital, most commonly difficulty urinating. This problem affected 1 in 11 women after discharge. A year after surgery two thirds of women reported feeling better (251; 72%), that the outcome met or exceeded their expectations (230; 66%), and that they would recommend the operation to a friend in a similar situation (239; 68%). Surgeons tended to be more optimistic about the effects of surgery; they were satisfied with the outcome in 176 (85%) cases and would again treat 245 (94%) of the women as they had done previously. Conclusions: Although surgery reduces the severity of stress incontinence it is not as effective as current textbooks suggest. Women considering surgery should be provided with more accurate information on the likelihood of an improvement in symptoms and the occurrence of complications, including postoperative pain. Urgency and urge incontinence should not be considered contraindications to surgery. The need for urodynamic assessment before surgery should be reappraised. Key messages Although surgery improves stress incontinence in most women (87%), only 28% are continent one year later The need for preoperative urodynamic testing should be reappraised Urgency and urge incontinence should not be considered contraindications to surgery Women considering surgery should receive more accurate information on the probability of an improvement in symptoms and possible complications There is a need for a rigorous, pragmatic, randomised trial of surgery for stress incontinence

Histological characteristics of the index lesion in whole-mount radical prostatectomy specimens: implications for focal therapy

It has been suggested that in multifocal prostate cancer (PCa), focal therapy to the largest (index) lesion is sufficient, because secondary non-index lesions are unlikely to contribute to disease progression. In this study, the role of PCa focality in selecting men for focal therapy was evaluated. A histopathological analysis of the index and non-index lesions of 100 consecutive radical prostatectomy specimens was carried out. Cases that would have been suitable for focal ablation were also evaluated. Tumours were more often multifocal (78%) and bilateral (86%). In total, 270 tumour foci were identified. In multifocal disease, tumour volume, Gleason score and pathological stage were almost invariably defined by the index lesion of the specimen; among the 170 satellite foci, 148 (87%) were <0.5 cm3 and 169 (99.4%) had Gleason score ⩽6. Using the defined criteria, 51% of men in this series would have been considered suitable for focal ablation of the index lesion. Histological features of poor prognosis in the prostate are associated with the index lesion. There is a high proportion of patients who may be suitable for focal therapy, and clinical trials of index lesion ablation should be considered as part of this therapeutic strategy.

Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09)

Summary Background Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. Methods In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. Findings 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12–31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7–14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0–15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and −0·16 mmol/L (−2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and −0·23 mmol/L (−3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). Interpretation Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. Funding Cancer Research UK, MRC Clinical Trials Unit.

Impact of surgery for stress incontinence on the social lives of women

Objective To assess the feasibility of collecting disease‐specific and generic data on the impact of surgery on the social lives of women with stress incontinence; to describe the social impact of surgery in a representative group; and to determine the effect of timing on the assessment of outcome.

Tumor focality in prostate cancer: implications for focal therapy

In recent years, there has been a growing interest in focal treatment for prostate cancer. Although widely used for the treatment of tumors of the breast and kidney, focal treatment for prostate cancer remains a controversial area. Criticism of focal prostate therapy has been based on the fact that prostate cancer is a multifocal disease. Until now, little attention has been paid to distinguishing between men with unifocal and those with multifocal disease because such information has little clinical relevance when treatment is aimed at the whole gland irrespective of the volume or number of cancers in the prostate. In this Review, we summarize existing knowledge and examine the issue of prostate cancer focality in the context of focal treatment.

Re-constructing masculinity following radical prostatectomy for prostate cancer.

Prostate cancer is common in older men. Surgical treatment involving removal of the prostate can result in temporary or permanent erectile dysfunction (ED) and incontinence and have a major impact on mens masculine identity. Seven men were interviewed about their experiences and concerns following prostatectomy, and the transcripts were analysed employing Foucauldian Discourse Analysis to identify the ways in which they constructed their masculinity. Participants drew upon four main discourses when discussing the impact of surgical treatment on their sense of masculinity: masculine identity and sexual activity, ED as a normative experience, mental resilience and vulnerability. Penetrative sex was constructed as central to a masculine identity, but inability to achieve this was normalised in terms of the ageing process. Stereotypically masculine qualities of emotional control and rationality were drawn on in describing their reaction to the diagnosis and treatment of cancer but they also experienced a new-found sense of physical vulnerability. The findings are discussed in terms of their implications for the clinical management of ED post-surgery and helping men adjust to life following treatment.

Human MUC1 Mucin: A Potent Glandular Morphogen

Human MUC1 mucin is a high‐molecular‐weight transmembrane glycoprotein, which is apically expressed in the majority of glandular epithelia. During embryonic development, changes in the pattern of MUC1 mucin expression coincide with the onset of glandular differentiation. This mucin is also frequently overexpressed and aberrantly glycosylated in carcinomas. To investigate the potential role of MUC1 mucin in morphogenesis, a full length MUC1 cDNA was transfected into murine mammary adenocarcinoma (410.4) and Madin‐Darby canine kidney (MDCK) cells. This generated four clonal cell lines. Western blotting, FACS analysis, and immunohistochemistry confirmed expression of MUC1. All four MUC1‐expressing clones demonstrated altered morphogenesis when cultured in three‐dimensional type I collagen gels. While parental and vector control 410.4 cells formed compact spherical structures, the MUC1‐expressing clones formed complex branching structures. Similarly, while parental and vector control MDCK cells formed small circumscribed colonies with a central lumen, the MUC1‐expressing clones formed elongated tubules. MUC1 expression was also associated with reduced cellular cohesion and enhanced migration on type I collagen‐coated surfaces for all except one of the clones, which expressed only low levels of MUC1 on the cell surface. These results show that MUC1 expression stimulates morphogenetic changes in two distinct epithelial cell lines. Taken together with previous observations on MUC1 expression in embryonic development and carcinomas, this finding suggests that MUC1 may induce changes in tissue architecture in both normal development and cancer. Copyright

Differentially expressed genes in hormone refractory prostate cancer: association with chromosomal regions involved with genetic aberrations.

Differential gene expression between the androgen sensitive human prostate cancer cell line LNCaP and an insensitive clonal variant, LNCaP-r, was demonstrated by suppression subtractive hybridization. Twenty-one sequences were identified of which 9 are homologous to known genes, 11 are represented by expressed sequence tags (ESTs), and 1 is novel. We present data for 5 of 7 sequences confirmed to be differentially expressed by Northern blot analysis and semiquantitative RT-PCR. Only one gene, fibronectin (FN), was highly overexpressed (>60-fold) in LNCaP-r cells, consistent with previously reported overexpression of FN in prostate cancer. Four sequences were down-regulated in LNCaP-r cells, including an inactive variant of the E2 ubiquitin conjugating enzyme (UEV-1), a novel metalloproteinase-related collagenase (PM5), and a potential tumor suppressor gene (breast basic conserved gene, BBC1). UEV-1 is multifunctional, regulates the cell cycle via cdk1, has homology to MMS2 and likewise functions as a DNA protection protein, and also has homology to TSG101. Aberrant splice variants of TSG101 occur frequently in both breast and prostate cancer, but its mechanism of action is unknown. FN, BBC1, and UEV-1 localize to regions of chromosomal aberration (2q3.4, 16q24.3, and 20q13.2, respectively) associated with advanced prostate cancer and thus may be highly relevant to disease progression.

Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first‐line hormonal therapy in patients with locally advanced or metastatic prostate cancer

To assess the hormonal effects of Fem7® (Merck, KGaA, Darmstadt, Germany) 100 µg transdermal oestrogen patches on men undergoing first‐line androgen‐deprivation therapy for prostate cancer.