Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2.

The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.

Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2.

Clinically relevant prostate cancer (PCa) is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle, primarily diabetes, characterised by hyperinsulinaemia and hyperglycaemia. IGFs and their binding proteins (IGFBPs) are important mediators of the effects of nutrition on growth and play a key role in the development of PCa. We used DU145, PC3 and LNCaP PCa cell lines to examine how hyperglycaemia altered their response to docetaxel. Trypan Blue dye-exclusion assay was used to determine the percentage of cell death. Protein abundance was determined using western immunoblotting. Levels of IGFBP2 were measured using an ELISA. IGFBP2 gene silencing was achieved using siRNA technology. DNA methylation was assessed using combined bisulphide restriction analysis. Acetylation status of histones H3 and H4 associated with IGFBP2 gene was assessed using chromatin immunoprecipitation assay. Hyperglycaemia reduced docetaxel-induced apoptosis by 40% for DU145 cells and by 88% for LNCaP cells. This reduced cell death was mediated by a glucose-induced up-regulation of IGFBP2, as silencing IGFBP2 negated the survival effect of high glucose. Glucose increased IGFBP2 via increasing the acetylation of histones associated with the IGFBP2 gene promoter. This finding could have important implications in relation to therapeutic strategies as epigenetic modulation could be reversible.

Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel.

BACKGROUND: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments. AIM: The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel. METHODS: DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT-PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting. RESULTS: The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with ß-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel. CONCLUSION: The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.

Optimal nutrition should improve the outcome and costs of radical cystectomy.

INTRODUCTION: Nutritional support has been demonstrated to improve recovery from radical cystectomy, but is expensive and when used inappropriately may actually increase the costs and morbidity of surgery. We sought to establish national patterns of practice with regard to feeding following cystectomy in the UK. AIMS AND METHODS: Following consultation with the specialist nutrition team, a questionnaire was designed to investigate the feeding strategy after cystectomy and dispatched by post to all UK urologists. RESULTS: The majority (60%) of respondents employed a traditional strategy of resting the bowel and feeding orally after bowel recovery. A minority used either early total parenteral nutrition (TPN; 18.5%) or enteral nutrition (6.5%), but a larger proportion (29%) felt enteral nutrition was the 'optimal' feeding regime. Only 30% used guidelines and 52% felt trials would help to establish a nutrition strategy following cystectomy. CONCLUSION: There is little evidence that TPN improves the outcome of cystectomy and it may actually increase morbidity and costs, whereas enteral nutrition may improve recovery. Despite this evidence TPN is widely used by urologists whereas enteral nutrition is used infrequently. Implementation of an evidence-based feeding regime after cystectomy is likely to reduce the morbidity and financial costs of cystectomy.

Serum amino-terminal propeptide of type 1 procollagen (P1NP) in prostate cancer: a potential predictor of bone metastases and prognosticator for disease progression and survival.

INTRODUCTION: To determine if amino-terminal propeptide of type 1 procollagen (P1NP) is reliable as a predictor of prostate cancer bone metastases and assess its value as a prognostic indicator of disease progression and survival. MATERIALS AND METHODS: A cohort of patients with prostate cancer between January 1999 and July 2001 were recruited. Prostate-specific antigen (PSA) and P1NP levels were measured. Two years following completion of recruitment, patient notes were reviewed for symptoms of bone metastases and survival. RESULTS: 24 negative and 12 equivocal or positive bone scans were reported for 36 recruited patients. Mean PSA values for patients with negative, equivocal and positive scans were 18.3, 24.9 and 122.5 ng/ml while mean P1NP for the same groups were 38.2, 73.4 and 119.9 ng/ml. For patients with equivocal and positive scan, mean P1NP with and without bone symptoms were 111.5 and 65.7 ng/ml while for surviving and dead patients the values were 63.9 and 120.8 ng/ml, respectively. CONCLUSIONS: Though this study involved a small number of patients, it demonstrates P1NP's potential as a predictor of bone metastases and a prognosticator for disease progression and survival.

A prospective evaluation of the management of acute pyelonephritis in adults referred to urologists.

In order to assess whether it is appropriate and clinically efficient to admit adults with 'clinically diagnosed' acute pyelonephritis (APN) under urologists, as is current practice in many NHS hospitals, a prospective study was undertaken over nine months in an NHS teaching hospital. Thirty-nine patients with clinical APN were admitted to the urology unit; all were pyrexial and 30 (77%) had typical features of rigor, flank pain and irritative lower urinary tract symptoms. Twenty-one (54%) had positive urine cultures, 31 (79%) had parenteral antibiotics, while another three (7%) had oral agents initially. The remaining five (14%) were continued on agents initiated by their GPs before admission. Thirty-three (85%) had imaging procedures with eight significant anomalies being noted. Urgent invasive intervention was required in only four (10%) patients; length of stay varied from one to 25 days. Uncomplicated moderate to severe APN in adults may be treated safely without the need for admission to the urology unit, either in the outpatient setting or on an acute admissions observation ward. Complicated cases requiring intervention can be transferred to the urologist once recommended investigations have been undertaken. This care pathway may help to reduce cancellations of elective urological cases and is likely to be more cost-effective for the NHS by reducing unnecessary admissions.

Oxygen free radicals and the penis.

Penile erection is dependent upon vascular smooth muscle relaxation in erectile tissue and penile arteries, the principal mediator of relaxation being nitric oxide (NO). Evidence from basic scientific studies indicates that oxidative stress mediated through the superoxide radical (superoxide) and other reactive oxygen species (ROS) may be central to impaired cavernosal function in erectile dysfunction (ED). Increased inactivation of NO by superoxide results in impaired penile NO transmission and smooth muscle relaxation. Furthermore, propagation of endothelial dysfunction by ROS may result in chronic impairment of penile vascular function, a process analogous to early atherogenesis. Indeed, ED and atherosclerosis are closely linked through shared risk factors. Given our current understanding of ED pathophysiology, antioxidants may be of benefit in both the short- and long-term. Evidence supporting the paradigm of antioxidant therapy for the prevention or treatment of ED is presented herein.

Investigation of upper tracts after resolution of symptoms due to ureteric calculi.

OBJECTIVE: To determine whether patients with proven ureteric calculi on IVU require repeat IVU after resolution of symptoms and passage of calculus on plain X-ray. METHODOLOGY: IVU reports for a 12-month period were obtained and notes and X-rays of those patients with ureteric calculi were reviewed. Presentation, management and subsequent imaging after resolution of symptoms were determined for each patient. All X-rays were reviewed by a uroradiologist. RESULTS: Fifty-eight patients were investigated for the study. All initial IVUs showed upper tract dilation or obstruction. Forty-three eventually passed their calculi spontaneously and of these, 18 had KUB, all of which showed passage of the calculus and 25 had repeat IVU, 22 of which were normal. The 3 abnormal IVUs showed persisting calculi which were visible on the plain film. Fifteen patients required surgical intervention and all had repeat IVU, of which 5 were abnormal. CONCLUSION: This study suggests that following resolution of symptoms due to ureteric colic, patients who pass their calculi spontaneously can be followed up by KUB. Only those with persistent calculi on KUB or those who have had surgical intervention require repeat IVU.