Transrectal high-intensity focused ultrasonography is feasible as a new therapeutic option for advanced recurrent rectal cancer: report on the first case worldwide.

High-intensity focused ultrasonography is the only completely non-invasive thermal therapy. To date its applications have been limited but clinical indications are expanding with enhanced technological advances that have increased the accuracy of targeting and decreased the duration of treatment times. We report its first use for rectal cancer.

Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer.

PURPOSE: Current androgen deprivation therapies for men with prostate cancer cause accelerated osteoporosis and a significant risk of osteoporotic fracture. We have recently shown that transdermal estradiol is an effective alternative for such patients. Here we report the impact of transdermal estradiol therapy on the bone mineral density of men with prostate cancer. MATERIALS AND METHODS: A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated with transdermal estradiol patches. Bone mineral density of the lumbar spine and the proximal femur was measured with dual-energy x-ray absorptiometry, and correlated with computerized tomography and isotope bone scan findings at 6-month intervals. RESULTS: In all measured regions bone mineral density increased with time. By 1 year mean bone mineral density +/- SEM had increased by 3.60% +/- 1.6% in the lumbar spine (p = 0.055), 2.19% +/- 1.03% in the femoral neck (p = 0.055), 3.76% +/- 1.35% in the Ward's region (p = 0.008) and 1.90% +/- 0.85% in the total hip (p = 0.031), respectively. Of 12 osteoporotic sites 4 had improvement based on World Health Organization grading. All other sites improved toward a better classification. CONCLUSIONS: Transdermal estradiol protects against bone loss in men with prostate cancer and may improve bone density in those at risk for osteoporotic fracture.

Inverse correlation between high level expression of cyclin E and proliferation index in transitional cell carcinoma of the bladder.

BACKGROUND/AIMS: Overexpression of the G1 cyclins, D1 and E, and/or downregulation of p27(Kip1) allow uncontrolled tumour cell proliferation. This study investigated the relation between these three cell cycle proteins and tumour proliferation in bladder cancer. METHOD: Nuclear expression of cyclin D1, cyclin E, and p27(Kip1) was determined immunohistochemically in 52 primary transitional cell carcinomas, and the Ki-67 proliferation marker was also assessed. For each protein, the percentage of positive tumour cell nuclei was determined and analysed as a continuous variable. RESULTS: Advancing tumour grade and pathological stage were accompanied by increasing proliferation indices, but decreasing p27(Kip1) and cyclin D1 expression, with no significant change in cyclin E expression. Overall, cyclin D1 and E expression did not correlate with proliferation. However, in cyclin D1 overexpressing tumours (> or = 5% nuclei positive), the level of cyclin D1 expression positively correlated with proliferation. The correlation between cyclin E expression and proliferation changed from positive to negative with increasing levels of cyclin E expression, accompanied by a coordinate increase in p27(Kip1) expression. Overall, there was an inverse association between p27(Kip1) expression and proliferation. However, a subset of tumours displayed high proliferation indices despite high p27(Kip1) expression. The G1 cyclin index (sum of the level of expression of cyclins D1 and E) correlated positively with proliferation in superficial but not muscle invasive tumours. This correlation was stronger when the G1 cyclin index was adjusted for p27(Kip1) expression. CONCLUSION: These findings support a role for these proteins in the proliferation, differentiation, and progression of bladder transitional cell carcinomas.

Transdermal estradiol therapy for advanced prostate cancer--forward to the past?

PURPOSE: Current hormonal therapies for prostate cancer are associated with significant morbidities, including symptoms of andropause and osteoporosis. Oral estrogens prevented many of these problems but were abandoned due to cardiovascular toxicity attributed to hepatic effect. In contrast, parenteral estrogens prevent first pass hepatic metabolism and substantially reduce cardiovascular risk, and long-term transdermal estradiol therapy is believed to be cardioprotective. We report preliminary results of a pilot study using transdermal estradiol therapy to treat men with advanced prostate cancer. MATERIALS AND METHODS: A total of 20 patients with advanced prostate cancer were enrolled in a before and after study that examined the impact of estradiol patches on hormones, disease, thrombophilia, vascular flow, osteoporosis and quality of life. RESULTS: Median followup is 15 months. Estradiol levels greater than 1,000 pmol./l. were achieved using 2 patches and higher levels were obtained by increasing the number of patches. All patients achieved castrate levels of testosterone within 3 weeks and had biochemical evidence of disease regression. One patient died of disease at 14 months and 1 cardiovascular complication occurred. Thrombophilic activation was avoided and vascular flow improved. Bone mineral density was significantly increased. Mild or moderate gynecomastia occurred in 80% of patients but no patient had hot flushes. All other functional and symptomatic quality of life domains improved. CONCLUSIONS: Transdermal estradiol therapy produced an effective tumor response. Cardiovascular toxicity was substantially reduced compared with that expected of oral estrogen, and other morbidity (gynecomastia) was negligible. Transdermal estradiol therapy prevented andropause symptoms, improved quality of life scores and increased bone density. Transdermal estradiol costs a tenth of current therapy cost, with the potential for considerable economic savings over conventional hormone therapies.

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.

Differential expression of cell death regulators in response to thapsigargin and adriamycin in Bcl-2 transfected DU145 prostatic cancer cells.

Functional overexpression of Bcl-2 has been reported to confer an anti-apoptotic potential in a variety of cell types. The role of Bcl-2 in epithelial cell-cycle control and in interactions with other cell-cycle regulators is not clearly understood. Its expression has been correlated with the hormono- and chemo-resistant phenotype in advanced prostate cancer. The aim of this study was to investigate the mechanisms through which Bcl-2 mediates increased cytotoxic chemoresistance by assessing alterations in the expression of cell death regulatory molecules. The DU145 human prostatic adenocarcinoma cell line was stably transfected with a Bcl-2 encoding expression plasmid. Two Bcl-2 transfectants, DKC9 and DKC11, were expanded for further study. The effects of Bcl-2 expression on cellular proliferation, cell death (+/- adriamycin or thapsigargin), and expression of cell-cycle/death regulators (p53, PCNA, Bax, Bak, Bcl-X(L)) were evaluated. Compared with controls, Bcl-2 transfectants showed no difference in the rate of proliferation, a decrease in p53 (approximately two-fold), an increase in Bax (approximately two-fold) and PCNA (approximately three-fold), and no change in the levels of Bcl-X(L) and Bak proteins. DKC9 and DKC11 also exhibited a significantly increased chemoresistance to adriamycin (0.0025-5 microM) and thapsigargin (0.0025-5 microM) compared with controls. In the presence of thapsigargin or adriamycin, levels of Bcl-2 and its heterodimeric partner Bax were elevated approximately two-fold with no change in Bak in Bcl-2 transfectants in contrast to controls, where Bak was increased (two-fold). This is the first study to demonstrate that Bcl-2 transfection modulates the expression of mutant p53, Bax, and PCNA in prostate cancer cells. Moreover, Bcl-2 overexpression conferred a significant cytotoxic chemoresistance and altered the balance of expression of death promoters (from Bak, a dominant death promoter in controls, to Bax) in response to thapsigargin and adriamycin.

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. Materials and methods The study comprised 30 samples from patients with benign prostatic hyperplasia (BPH) and 82 with prostate cancer. Immunohistochemistry was used to assess the expression of COX-1 and -2, and 13 samples were also assessed using immunoblotting (six BPH and seven cancers). RESULTS: For both BPH and prostate cancer, COX-1 expression was primarily in the fibromuscular stroma, with variable weak cytoplasmic expression in glandular/neoplastic epithelial cells. In contrast, COX-2 expression differed markedly between BPH and cancer. In BPH there was membranous expression of COX-2 in luminal glandular cells and no stromal expression. In cancer the stromal expression of COX-2 was unaltered, but expression by tumour cells was significantly greater (P = 0.008), with a change in the staining pattern from membranous to cytoplasmic (P < 0.001). COX-2 expression was significantly higher in poorly differentiated than in well differentiated tumours (P < 0.001). These results were supported by immunoblotting, which showed similar levels of COX-1 in both BPH and cancer, but four times greater expression of COX-2 in cancer than in BPH. CONCLUSION: This is the first study to assess the co-expression of COX-1 and COX-2 proteins in benign and malignant human prostates, and showed the induction and significantly greater expression of COX-2 in cancer, which was also associated with tumour grade. The regular use of nonsteroidal anti-inflammatory drugs is associated with a reduced incidence of cancers. The present results provide the basis for a potential role for COX-2 inhibitors in the prevention and treatment of prostate cancer.

Cost-benefit analysis of the use of TBT: the case for a treatment approach.

The current climate of hostility towards the use of tributyltin (TBT) as an active ingredient in ship anti-fouling paint appears to be based on a very biased assessment of its environmental impact. While many national and international regulatory agencies are moving towards further restriction, and a complete ban is under active discussion, a number of factors appear to have been ignored. The economic impact of a ban on TBT when no adequate substitute exists could be substantial. Environmentally, consequences would include a substantial increase in the consumption of fossil fuel, with corresponding increases in carbon dioxide and sulphur dioxide emissions; the construction of more vessels; the transfer of ship-building, ship-repairing and ship-breaking activities from well-regulated to unregulated or under-regulated areas in the developing world; and a shift from sea transport to less environmentally acceptable forms of transport. Experience in Europe and other parts of the developed world shows that existing restrictions, where they are properly enforced, are probably adequate to alleviate the environmental damage associated with TBT. Some existing legislation acts to inhibit the search for effective substitutes. The environmental benefits of TBT have been ignored. Little thought has been given to a technical, rather than a legislative solution to controlling TBT inputs to the environment. A method is described for treating TBT-contaminated wastewaters, which has been successfully tested in prototype at full scale. Legislative measures against TBT will do nothing to address the problem of the existing backlog of contaminated material, nor even to permit the IMO proposal for the removal of TBT from all ships by 2008 to be successfully concluded in an environmentally safe manner, since no provision has been made for the disposal of the existing TBT; most probably it will be dumped in environmentally sensitive, unregulated areas in the developing world.

Development of the fertility adjustment scale.

OBJECTIVE: To develop a standardized measure of psychological adjustment to infertility. DESIGN: A cross-sectional two-group comparison study. SETTING: Two specialized fertility clinics in large teaching hospitals. PATIENT(S): Fifty men and 50 women undergoing evaluation and/or treatment of fertility problems. INTERVENTION(S): The Fertility Adjustment Scale was administered with the Hospital Anxiety and Depression Scale as a measure of concurrent validity. MAIN OUTCOME MEASURE(S): Scores on the Fertility Adjustment Scale and the Hospital Anxiety and Depression Scale. RESULT(S): Scores on the Fertility Adjustment Scale were distributed normally. Split-half and internal consistency were high. A significant correlation with measures of mood, anxiety, and distress provided evidence of concurrent validity. CONCLUSION(S): Preliminary results suggest that this measure will be a useful tool in assessing psychological reactions to fertility problems and outcomes of treatment.

Role of the Bcl-2 gene family in prostate cancer progression and its implications for therapeutic intervention.

Prostate cancer (PC) is an escalating health burden in the western world. A large number of patients still present with extraprostatic (i.e., T3/T4, N0, M0/M1 or any T category and M1 disease or involved lymph nodes) and therefore incurable disease. Since the work of Huggins in 1940, there have been no major therapeutic advances and androgen ablation remains the best treatment option for extraprostatic androgen-responsive PC. Eighty to ninety percent of PC patients respond well to this form of treatment initially. After a median time of approximately 2 years, however, relapse to an androgen-independent (AI) state occurs, followed by death after a further median 6 months. Androgen ablation is rarely curative. The major molecular defect in extraprostatic and AI PC is the inability of PC cells to initiate apoptosis in response to a variety of stimuli, including different forms of androgen ablation and cytotoxic agents. The balance between cellular proliferation and cell death is regulated by multiple genes or families of genes through the cell cycle. The exact mechanisms governing this intricate and complex process are as yet not fully understood. One family of genes involved in cell survival/death control is the Bcl-2 gene family, which consists of homologous proteins that function to regulate distal and crucial commitment steps of the apoptotic pathway. The Bcl-2 family constitutes both agonists and antagonists of apoptosis that function at least in part through protein-protein interactions between various members of the family. The final outcome depends on the relative ratio of death agonists and antagonists. Bcl-2 expression has been closely associated with the AI phenotype of PC. Cytotoxic chemotherapy may be used as palliative therapy in AI PC but has not been found effective. Most chemotherapeutic cytotoxic agents induce apoptosis in cancer cells by direct and indirect action on the cell cycle. In vitro and in vivo studies have established that Bcl-2 expression confers an antiapoptotic activity against androgen withdrawal and cytotoxic chemotherapy. It thus offers a tempting potential target for therapeutic manipulations of PC.

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.

What determines the choice of procedure in stress incontinence surgery? The use of multilevel modeling.

The purpose of this study was to identify the determinants of choice of surgical procedure (anterior colporrhaphy, colposuspension, or needle suspension) to treat stress incontinence in women. We used multilevel modeling of data on 271 patients in 18 hospitals in England in 1993-94. Patient-related factors included sociodemographic details, anatomical diagnosis, symptom severity, symptom impact, previous treatment, parity, comorbidity, and general health status. Surgeon-related factors were specialty, grade, and annual volume of procedures undertaken. Hospital teaching status was considered. Some patient-related factors were associated with choice of procedure: women with a concomitant genital prolapse, with a history of high parity, and with no previous nonsurgical treatment were more likely to undergo an anterior colporrhaphy than a colposuspension or needle suspension (although this finding could be confounded by surgical specialty). In addition, women were more likely to be treated by colposuspension if their surgeon specialized in incontinence surgery (measured by annual volume of cases). Finally, being treated by needle suspension depended on there being a consultant surgeon familiar with the procedure at the hospital attended. While choice of surgical procedure depends partly on the patient's anatomical diagnosis, it is also dependent on the specialty of the surgeon whom she consults and the hospital that she attends. This variability, in turn, could have implications for the patient (as the relative effectiveness of the different procedures is unknown) and for the purchasers of care (as the relative cost-effectiveness of procedures is also unknown).

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. DESIGN: Longitudinal study; questionnaires before and three, six, and twelve months after surgery. SETTING: Eighteen hospitals in North Thames region. PARTICIPANTS: Four hundred and forty-two women undergoing surgery for stress incontinence between January 1993 and June 1994. MAIN OUTCOME MEASURES: Post-operative recovery time, stress incontinence symptom impact index, activities of daily living, and cost of protection. RESULTS: Post-operative recovery was uneventful for most women, but three months after surgery 24% of those in paid employment beforehand were still on sick or unpaid leave. Most women (75%) reported that stress incontinence had less adverse impact on their lives three months after surgery, though 18% reported no change, and 7% felt life was worse. The likelihood of improvement was similar regardless of whether pre-operative urodynamic studies had been conducted. The extent of improvement was dependent on pre-operative severity. Similar findings were obtained six and twelve months after surgery. After an initial slight but nonsignificant deterioration in their ability to carry out activities of daily living, women gained a slight benefit from surgery (proportion with no or only slight limitation rose from 72% to 82%; P=0.0001). The mean cost of protection (pads and towels) fell from 8.59 pound sterling a month before surgery to 2.99 pound sterling a month one year after surgery, by which time 68% of women were not using protection. In contrast, 11% were still spending over 10 pound sterling a month. CONCLUSIONS: It is possible to collect standard data on the impact of surgery on social functioning and, thus, provide women with better information on likely outcomes. The benefits of pre-operative urodynamic investigations need to be assessed. The stability of the outcome measures over the first post-operative year suggest that outcomes need to be assessed only once and at any time from three to twelve months after the operation.

Molecular and cellular biology of prostate cancer.

Prostate cancer is an enigmatic disease. Although prostatic-intraepithelial neoplasia appears as early as the third decade and as many as 80% of 80 year old men have epithelial cells in their prostate that fit the morphological criteria for cancer, only about 10% of men will ever have the clinical disease and less than 3% will die from it. There have been no significant proven interventions which have altered the natural history of the disease since hormone down regulation was introduced in the 1940s and new research has been poorly supported. There is however an urgent need to develop new criteria to distinguish those patients with localised disease who will benefit from intervention from those that do not require it or who will have occult extra prostatic metastases. Similarly, there is an urgent need to develop new treatments for those in whom the disease is extra-prostatic and therefore incurable by conventional treatments. This review covers the latest developments in epidemiology, cellular and molecular biology including new areas such as ion channels in the field of prostate cancer.