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.

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.

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.

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.

Magnetic resonance imaging in the staging of renal cell carcinoma.

A prospective study has been carried out to examine the role of magnetic resonance imaging (MRI) in the investigation of renal cell carcinoma in 24 patients. In all cases the inferior vena cava (IVC) was well demonstrated with MRI. In 14 out of 15 patients where surgical correlation was available, the MRI and operative staging were in agreement. Magnetic resonance imaging and computed tomographic (CT) staging were in agreement in 16 out of the 17 patients where both were performed. In one case, CT suggested hepatic invasion but this was found not to be present on MRI and at operation. Magnetic resonance imaging also provided substantial additional information in three patients, including two cases where MRI demonstrated a patent IVC that appeared occluded on CT (one of which also had vertebral metastases seen on MRI but missed on CT) and one case where CT failed to demonstrate minimal involvement of the IVC. Magnetic resonance imaging is an accurate means of staging renal cell carcinoma with clear advantages over CT. In no case in this series was inferior vena cavography found to be necessary.

A departmental audit of patients with bladder cancer.

In keeping with the recent demands of the Department of Health for medical audit in clinical practice, an audit was undertaken of the management of bladder cancer patients in a large department of urology having three consultants with varied approaches of management. This study revealed interesting controversial areas for further scrutiny. For example, the poor prognosis of grade 3 T1 tumours with and without associated carcinoma-in-situ (CIS) and the speed of progression to invasive disease have indicated that a change to a more aggressive approach to the management of these tumours is necessary. High recurrence rates at the site of the original tumour (60%) and the presence of CIS also indicate the need for expert and thorough initial tumour assessment. The delays in diagnosis and treatment lend further support to the need for a 'haematuria clinic' to minimise such delays, which may influence prognosis. To reduce the occurrence of systematic errors in the recording, follow-up and surveillance of patients with bladder cancer, a protocol is suggested for a structured approach to optimise results, particularly in the poor prognostic categories.

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.

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.

Appendicitis and occult carcinoma of the caecum.

Appendicitis can occur rarely in association with carcinoma of the caecum, particularly in the elderly. If this possibility is not appreciated and thorough laparotomy is not carried out at the time of initial surgery, an early malignant lesion may go unrecognised. In this situation, if appendicectomy is performed, it will need to be revised to a right hemicolectomy at a later date. Survival chances are then affected adversely due to the possibility of early dissemination of malignant disease through the breaching of intestinal integrity and tumour cell spillage. Two cases are reported where carcinomatous recurrence occurred in the appendicectomy wound, probably as a result of initial appendicectomy at which the co-existent caecal neoplasm was missed.

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.

Dialysis in patients with upper urinary tract transitional cell carcinoma.

In some patients with primary malignant disease of the kidney the only way of achieving a cure may involve radical surgery. If the tumour is bilateral or involves a solitary kidney, renal failure may be unavoidable. The role of dialysis and transplantation in these patients following "curative" cancer surgery is not clear. A review of the literature and experience with 4 patients who ultimately had bilateral nephrectomies for multiple recurrent upper tract urothelial malignancy is reported. These 4 patients remained free of tumour recurrence on dialysis at 5, 8, 12 and 72 months respectively since commencing dialysis, although 2 have died from unrelated causes. It would seem reasonable to offer dialysis followed by subsequent transplantation in this group of patients after a period of 1 to 2 years has elapsed without any evidence of malignant recurrence.

Intravesical foreign bodies: five-year review.

All manner of foreign bodies have been extracted from the bladder. Introduction into the bladder may be through self-insertion, iatrogenic means or migration from adjacent organs. Extraction should be tailored according to the nature of the foreign body and should minimise bladder and urethral trauma. Complete extraction should also be confirmed by panendoscopy at the end of the extraction procedure. A 5-year review of our experience in this field has been conducted and the management and complications of intravesical foreign bodies are described. Of the 15 patients presenting to this department, 11 presented acutely and 4 presented with chronic symptoms due to complications which arose later. The possibility of an intravesical foreign body should be considered in any patient with chronic unexplained lower urinary tract symptoms.

Erythrocyte stearic to oleic acid ratio in prostatic carcinoma.

The red cell membrane stearic acid to oleic acid ratio was analysed in 34 men with histologically proven carcinoma of the prostate and distant metastases. This ratio was expressed as the saturation index (SI). A mean SI of 0.97 was found in control patients without evidence of any malignancy whereas all patients with advanced prostatic cancer showed a reduced stearic to oleic acid ratio (mean SI 0.466). Untreated patients had a significantly lower SI (mean 0.36) than those who had responded to hormonal therapy (mean 0.547; P less than 0.0001). A drop in SI correlated well with more advanced disease as judged by radiological findings and serum PSA. It is suggested that red cell membrane SI correlates well with radiological and biochemical markers of advanced prostatic carcinoma and may be used as a marker to assess progress and response to treatment.

Surgical management of the renal manifestations of von Hippel-Lindau disease: a review of a United Kingdom case series.

OBJECTIVE: To review the results of nephron-sparing surgery in a group of patients with von Hippel-Lindau (VHL) disease, a rare familial cancer syndrome which is dominantly inherited and predisposes affected individuals to developing various tumours, including haemangioblastomas of the retina and central nervous system, and multicentric renal cell carcinoma (RCC). PATIENTS AND METHODS: The 11 patients (seven men and four women, age range 27-62 years) assessed had been referred for surveillance to the Department of Clinical Genetics, Addenbrooke's Hospital, often having presented with neurological or ocular manifestations of the disease. Their case notes were reviewed to assess the results of conservative surgery. Five patients had more than one parenchymal-sparing operation (either partial nephrectomy or enucleation, i.e. removal of a malignant lesion with a 0.5 cm rim of normal tissue) while four had bilateral procedures. At the time of surgery, co-existent cysts were aspirated to allow a more accurate definition on computed tomography during follow-up. RESULTS: At a mean follow-up of 60 months after surgery, eight patients were alive with good renal function. Three patients were alive with paraplegia or paraparesis from spinal cord lesions. The three patients who died (aged 50, 40 and 31 years) were diagnosed when RCC was already advanced and renal tissue-preserving surgery was not possible. CONCLUSIONS: Nephron-sparing surgery may be justified because morbidity is reduced in patients whose quality of life may already be compromised by neurological and other problems, and because the lesions of RCC are often small, enucleation may also be justifiable in the attempt to conserve renal tissue and delay disease progression.

Imaging assessment of uncomplicated bladder outflow obstruction.

To assess the impact of the use of plain X-ray films and ultrasound examinations on clinical decision-making in patients referred with symptoms of bladder outflow obstruction. Patients with symptoms of bladder outflow obstruction were recruited prospectively. After clinical assessment they underwent standard investigations of plain X-ray of the kidneys, ureters and bladder, and upper and lower urinary tract ultrasound. A management decision was made on the basis of all results. These decisions were then reviewed with specific reference to radiological findings to assess the role of imaging in the decision-making process. A total of 320 men were recruited for the study. X-ray of the kidneys, ureters and bladder detected 10 upper tract calculi, none of which has required active intervention to date. Four bladder calculi were detected. Two of these were also seen on ultrasound scan: one was small and insignificant, the other had caused microscopic haematuria, necessitating cystoscopy regardless of the X-ray findings. Upper tract ultrasound revealed abnormalities and anatomical variants which did not affect management. Four patients had upper tract dilatation but these had already had surgery planned on the basis of other investigations, including residual urine volume determination by lower tract ultrasound. Lower urinary tract ultrasound should be the only routine imaging used in the initial assessment of patients with bladder outflow obstruction, with consequent implications of reduced patient stress and reduced investigation cost.

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.

Epidemiology of transitional cell carcinoma of the bladder: profile of an urban population in the south-west of England.

OBJECTIVES: To produce an epidemiological profile of patients with transitional cell carcinoma (TCC) of the bladder living in the city of Bristol (south-west England), to determine if TCC tumorigenesis is linked to possible risk factors (occupational exposure, cigarette smoking, alcohol consumption and coffee consumption) and to assess phenotypic acetylation status and thus determine whether there may be a genetic component to tumour development. PATIENTS AND METHODS: This cross-sectional observational epidemiological study recruited both cases and controls from one-stop haematuria clinics, providing two groups with a similar age and sex distribution. Before diagnosis, all patients were interviewed by the same researcher and results recorded on a specially designed database questionnaire, to eliminate both recall and investigator bias. Metabolic studies were also performed before diagnosis. RESULTS: There were significant associations for occupational exposure, cigarette smoking, and beer consumption (but not wine or spirits), but no significant association with coffee consumption. Slow acetylation status also conferred an increased risk. There were linear trends in terms of dose-response for both beer and cigarette consumption, although this was significant only for cigarettes. There was no difference in risk between the use of filtered or unfiltered cigarettes. CONCLUSION: Occupational exposure and cigarette smoking have been well documented as risk factors in the development of TCC of the bladder, as has slow acetylation status. There are very few studies linking bladder cancer with alcohol consumption. It is important to subdivide types of alcohol consumed when considering this factor in an epidemiological study. In the case of beer, methods used by different brewing processes may also contribute to differences found, were such a study to be performed on a national scale.

Urological audit: the role for an aggressive approach to high grade superficial bladder tumours.

A retrospective study was undertaken of the different treatment modalities for bladder tumours under the care of 3 consultants in the urology department of a district general hospital. The aim was to review the results of the various forms of treatment. In all, 261 patients' case records were reviewed and 19 variables extracted. There was an average delay of 4.2 months from the onset of symptoms to the initial cystoscopy. Over 50% of high grade tumours were invasive on initial presentation (G3T2/G3T3). A range of treatments for the more aggressive tumours was adopted by the urologists, ranging from a conservative resection (TURBT) to an aggressive approach (cystourethrectomy) at the earliest sign of progression. A strong association between aggressive treatment and higher survival was noted. This study has proved valuable in demonstrating to the urology team the value of routine audit and questioning "established" surgical practice. As a result, a more standard regime for the treatment of bladder tumours has been advocated and a prospective randomised controlled trial will be introduced.

An immunohistochemical and prognostic evaluation of cathepsin D expression in 105 bladder carcinomas.

Cathepsin D is a widely expressed aspartyl lysosomal protease. Clinical studies in several tumor types have shown a strong correlation between cathepsin D expression and tumor progression. In breast carcinoma, its expression is an independent prognostic factor associated with an increased risk of death. However, there have been no studies evaluating cathepsin D in bladder tumors. Therefore, the aim of this study was to determine the pattern of expression of cathepsin D in a large series of bladder carcinomas and assess its role as a prognostic factor against established variables. The tumors from 105 patients (median age 73) (median follow-up 26 months) with transitional cell carcinoma of bladder were examined. Forty-nine patients had superficial tumors (16 pTa; 33 pT1), 56 had invasive tumors (14 pT2; 42 pT3); there were 35 grade 1/2 tumors and 70 grade 3 tumors. These were stained by a standard immunohistochemical technique with an anti-cathepsin D monoclonal antibody. All 4 normal bladder specimens were positive for cathepsin D. Fifty-four tumors (51%) were positive for cathepsin D and 51 (49%) were negative. Chi square analysis showed a significant positive relationship between negative cathepsin D expression and stage (p < 0.0005), grade (p < 0.0001) and tumor morphology (p = 0.001). There was no relationship between cathepsin D expression and tumor ploidy (p > 0.1) or patient age (p = 0.09). Univariate analysis of disease-free and overall survival showed that negative cathepsin D expression (p = 0.01 and p = 0.0003 respectively), stage (p = 0.004 and p < 0.005 respectively) and grade (p = 0.02 and p = 0.0007 respectively) were associated with significantly worse prognosis. However, in a multivariate analysis of age, stage, grade and cathepsin D expression, only stage remained significant for overall survival (p < 0.005). The observed result for cathepsin D in the univariate analysis is probably due to its strong association with grade and stage. Nevertheless, cathepsin D status was able to provide additional prognostic information for overall survival in invasive tumors when stratifying for grade (p = 0.047), which suggests that it might provide additional prognostic data within particular tumor stages.