Aim/Background: Embraced when discovered by Huggins in 1940, 'hormone therapy' (androgen deprivation therapy (ADT)) for advanced prostate cancer, using oral estradiol (E2) was abandoned following data revealing good cancer specific but poor overall survival. Replaced by Luteinizing Hormone Releasing Hormone analogues (LHRHa), testosterone (T), but also E2, were suppressed to castrate levels. Toxicities resulted, remaining clinically and financially burdensome. The Phase III PATCH (Prostate Adenocarcinoma Trans-Cutaneous Hormones) trial, re-explores benefits and toxicities of E2 (transdermally) vs LHRHa. Transdermal E2 offers single medication effective both as ADT yet simultaneously mitigating toxicity. PATCH has enabled new hypotheses concerning sex hormone deficiency to be addressed.Methods: Summaries of sub-studies include: Cognitive: previously well men in the 3-12 months of LHRHa ADT achieving castrate T were divided into 2 groups, impaired/not, (they, family/friends were asked re changes consistent with cognitive impairment). They underwent complex neuro-psychometric testing, positron emission tomography scanning and structural/functional magnetic resonance imaging. Odour: 10 men starting LHRHa ADT provided axillary sweat on t-shirts worn over 2 successive nights pre and 3 months post-treatment. Non-cancer controls provided samples for comparison. Sweat samples were frozen at -80'C until rated simultaneously for masculinity, attractiveness and intensity by adult females. Bone: Dual Energy Xray Absorpiomery (DEXA), Computed Tomography (CT) scans performed at corresponding time points were identified (n = 20). Bone mineral density (BMD), bone volume fraction (BVF) metrics and finite-element analysis (FEA) for digital strength is underway.Results: Cognitive: Preliminary results suggest memory, executive function deficits plus diffuse cortical neuroinflamation.Odour: data are currently being analyzed.Bone: Comparisons made between BMD, BVF and FEA bone strength, potentially suggest superiority of CT to assess fracture risk.Conclusions: C: PATCH reflects potential for addressing hypotheses additional to main primary and secondary end-points of a large clinical trial through design and performance of novel sub-studies.Clinical trial identification: NCT02187120Disclosure: All authors have declared no conflicts of interest. Aim/Background: Embraced when discovered by Huggins in 1940, 'hormone therapy' (androgen deprivation therapy (ADT)) for advanced prostate cancer, using oral estradiol (E2) was abandoned following data revealing good cancer specific but poor overall survival. Replaced by Luteinizing Hormone Releasing Hormone analogues (LHRHa), testosterone (T), but also E2, were suppressed to castrate levels. Toxicities resulted, remaining clinically and financially burdensome. The Phase III PATCH (Prostate Adenocarcinoma Trans-Cutaneous Hormones) trial, re-explores benefits and toxicities of E2 (transdermally) vs LHRHa. Transdermal E2 offers single medication effective both as ADT yet simultaneously mitigating toxicity. PATCH has enabled new hypotheses concerning sex hormone deficiency to be addressed. Methods: Summaries of sub-studies include: Cognitive: previously well men in the 3-12 months of LHRHa ADT achieving castrate T were divided into 2 groups, impaired/not, (they, family/friends were asked re changes consistent with cognitive impairment). They underwent complex neuro-psychometric testing, positron emission tomography scanning and structural/functional magnetic resonance imaging. Odour: 10 men starting LHRHa ADT provided axillary sweat on t-shirts worn over 2 successive nights pre and 3 months post-treatment. Non-cancer controls provided samples for comparison. Sweat samples were frozen at -80'C until rated simultaneously for masculinity, attractiveness and intensity by adult females. Bone: Dual Energy Xray Absorpiomery (DEXA), Computed Tomography (CT) scans performed at corresponding time points were identified (n = 20). Bone mineral density (BMD), bone volume fraction (BVF) metrics and finite-element analysis (FEA) for digital strength is underway. Results: Cognitive: Preliminary results suggest memory, executive function deficits plus diffuse cortical neuroinflamation.Odour: data are currently being analyzed.Bone: Comparisons made between BMD, BVF and FEA bone strength, potentially suggest superiority of CT to assess fracture risk. Conclusions: C: PATCH reflects potential for addressing hypotheses additional to main primary and secondary end-points of a large clinical trial through design and performance of novel sub-studies. Clinical trial identification: NCT02187120 Disclosure: All authors have declared no conflicts of interest.

Active surveillance has been recommended by the National Institute for Health and Clinical Excellence (NICE) as a primary option for patients with low risk, localized prostate cancer. The objective of this study is to evaluate the evolution of pathologic outcomes in men undergoing radical prostatectomy prior to and after NICE guidelines.

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.

OBJECTIVE:To report the influence of transdermal oestradiol therapy on the vascular dynamics of men with advanced prostate cancer.PATIENTS AND METHODS:Twenty patients with newly diagnosed locally advanced or metastatic prostate cancer (10 each) were treated using transdermal oestradiol patches. The vascular flow was assessed 6-monthly before and during a year of therapy using arterial and venous Doppler and duplex ultrasonography, arterial and venous photoplethysmography and opto-electronic plethysmography.RESULTS:Arterial flow, as measured by the mean and peak systolic velocities and photoplethysmography, significantly increased over time. Arterial compliance initially decreased but had normalized after 12 months. The venous variables were unaffected. As a result, the total limb blood flow and the capillary filtration rate were significantly increased.CONCLUSION:Transdermal oestradiol therapy causes an increase in arterial but not venous flow, and an initial decrease in arterial compliance, which adapts to the physiological range with time. It is possible that these changes may account for the increase in cardiovascular toxicity seen in the early phase of oestrogen therapy, and the cardioprotective effect that accrues thereafter.

Trefoil factor family (TFF) domain peptides, products of mucin-secreting epithelial cells, are thought to influence mucosal integrity. Molecular studies revealed that mammalian TFFs lack transmembrane domains. Using immunocytochemistry and FACS analysis we demonstrated the association of TFF1 with the cell membrane in MCF-7 (a breast adenocarcinoma cell line), and tested the hypothesis that glycosylphosphatidylinositol (GPI) linkage is the mechanism for this association. Cleavage of GPI anchorage using phospholipase C did not affect TFF1 binding to the cell membrane. Our results demonstrate for the first time that TFF1 is associated with the cell membrane of MCF-7 cells and is not linked via a GPI anchor.

We have recently demonstrated that human TFF2 inhibits apoptosis in the non-TFF2 expressing breast adenocarcinoma cell line MCF-7. In this study we examined the impact of TFF2 and an anti-TFF2 antibody (hSP3) on the survival of other human adenocarcinoma cell lines; TFF2-positive (LS174T and SW480) and TFF2-negative (MCF-7 and T47D). Addition of TFF2 protected the (TFF2–) lines but had no effect on those constitutively expressing TFF2. Blocking with hSP3 significantly increased apoptosis in the (TFF2+) cell lines with minimal effect on the (TFF2–) cells. Our results show that the cytoprotective effect of TFF2 seen in MCF-7 cells is not cell line-specific and can be abrogated by inhibition of its expression.

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.

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.

Androgen independence is the major cause of endocrine therapy failure in advanced prostate cancer (PC). To examine the effects of human androgen receptor (AR) expression on growth of human PC cells, transfection of full-length AR cDNA in an androgen-insensitive human prostatic adenocarcinoma cell line (DU145) was performed. Transcriptional activity of AR was confirmed by the MMTV luciferase assay and AR expression was assessed by reverse transcriptase polymerase chain reaction, Western blotting, and immunocytochemistry. Two stable transfectant cell lines expressing functional AR were established and passaged over 60 times. Under standard culture conditions, AR expression in transfected cells was predominantly cytoplasmic. Exposure to dihydrotestosterone (DHT; 60 pM-10 nM) resulted in a rapid (maximal at 30 minutes) translocation of AR to the nucleus. Treatment with DHT (5 nM) caused a significant reduction in cell-cell adhesion and aggregation accompanied by a decrease in E-cadherin expression. This was associated with up to 40% inhibition of proliferation and approximately two-fold increase in apoptosis. These results suggest that gene transfer-mediated AR expression in DU145 cells confers sensitivity to DHT, modulates cell-cell adhesion through E-cadherin, and suppresses cell growth by inhibiting proliferation and promoting apoptosis. This provides a model for studies of AR-regulated cell signalling and identification of novel androgenregulated genes in PC.

This study examines the coexpression of MUC1 mucin and trefoil factor 1 (TFF1) and their relationship to progression of renal cell carcinoma (RCC). Immunohistochemistry was performed on tumor and adjacent normal tissue from clear-cell RCC (n = 60) and tissues from normal controls (n = 5) using a set of well-characterized monoclonal antibodies recognizing different epitopes of MUC1 and TFF1. Results of immunohistochemistry were compared with clinical parameters, including tumor grade, tumor size, presence of metastasis, and progression-free survival of patients after surgery. In normal tissue, MUC1 and TFF1 were absent from the normal proximal tubular epithelium but were identified in distal and collecting tubular epithelium. In RCC, increased MUC1 expression positively correlated to tumor progression. MUC1 recognized by HMFG1 was associated with large tumor size (P < .05), distant metastasis (P < .05), and invasion of large veins (P < .05). Expression of the under-glycosylated form of MUC1 recognized by SM3 was found to correlate to time to progression (recurrence, metastasis, or death of patient; P < .001). Expression of TFF1 did not significantly correlate with any prognostic parameters. However, there was a significant correlation (P < .01) between TFF1 and MUC1 expression (HMFG2 epitope) in RCCs. These results are consistent with the following conclusions: (1) MUC1 may be an independent prognostic marker in RCC; (2) TFF1 is frequently coexpressed with MUC1 and may act synergistically; and (3) RCC may originate from distal tubular epithelium.