Systematic review of the safety and efficacy of osseointegration prosthesis after limb amputation.

BACKGROUND: Osseointegration, an approach for direct skeletal attachment of a prosthesis to an amputated limb, may address many of the problems associated with socket prostheses. The safety of osseointegration remains uncertain. The aim of this study was to summarize evidence on functional and clinical outcomes, as well as adverse effects of osseointegration for patients with a limb amputation. METHODS: MEDLINE, Embase, Web of Science and the Cochrane Library were searched to April 2018. Eligible studies were observational, case and qualitative studies, and RCTs conducted in patients with a limb amputation, who were managed with osseointegrated prostheses and had follow-up data. RESULTS: Twenty-two eligible articles comprising 13 unique studies were included. No RCT was identified. Apart from three case reports that comprised one to five patients, the sample size of studies ranged from 11 to 100 participants. All relevant studies reported improvement in functional outcomes (walking ability, prosthetic use and mobility), satisfaction and quality of life following osseointegration, compared with their preoperative status or when using a conventional socket prosthesis. Infection rates ranged from 1 (95 per cent c.i. 0 to 5) to 77 (59 to 88) per cent. The majority of infections were described as low-grade soft tissue or superficial infections related to the skin-implant interface, and were treated effectively with antibiotics. None of the studies reported additional amputation or death as a result of osseointegration. CONCLUSION: Osseointegration after limb amputation improves prosthetic use, comfort when sitting, walking ability, mobility, gait and quality of life. However, it is associated with an increased risk of soft tissue infection.

A systematic review of PFE pre-prostatectomy.

Male Stress Urinary Incontinence is a complication post robotic radical prostatectomy. This is a major problem that needs to be solved, since it has great impact on quality of life affecting the patient's physical activity and social well-being. A systematic review relating to literature on impact of preoperative PFE on continence outcomes for patients undergoing prostatectomy was conducted. The search strategy aimed to identify all references related to pelvic floor exercises and post-prostatectomy. Search terms used were as follows: (Pelvic floor exercises) AND (incontinence) AND (prostatectomy). The following databases were screened from 2000 to September 2017: CINAHL, MEDLINE (NHS Evidence), Cochrane, AMed, EMBASE, PsychINFO, SCOPUS, Web of Science. In addition, searches using Medical Subject Headings (MeSH) and keywords were conducted using Cochrane databases. Two UK-based experts in prostate cancer and robotic surgery were consulted to identify any additional studies. In the 6 months following surgery, the continence rates, as defined by the use of one pad or less per day, were 94% (44 of 47) and 96% (48 of 50) in the PFE and biofeedback groups and control groups (PFE alone), respectively (P = 0.596) (Bales et al. in Urology 56: 627-630, 2000). This demonstrates preoperative PFE may improve early continence after RP. Geraerts et al. (Eur Urol 64:766-772, 2013) demonstrated the "incontinence impact" was in favour of a group with PFE at 3 and 6 months after surgery. This demonstrates again the advantage of preoperative PFE. Cornel et al. [World J Urol 23:353-355, 2005] determined the benefit of starting pelvic floor muscle exercise (PFE) 30 days before RP and of continuing PFE postoperatively for early recovery of continence as part of a randomised, prospective study (Moher quality A). This demonstrated preoperative PFE may improve early continence and QoL outcomes after RP. Post-prostatectomy incontinence is a bothersome complication of radical prostatectomy [Chughtai et al. in Rev Urol 15:61-66, 2013]. Weak pelvic floor muscles compromised normal pelvic floor function and led to urinary incontinence and erectile dysfunction. Strengthening the pelvic floor muscles was shown to significantly improve post-prostatectomy urinary continence, post-micturition dribble and erectile function. It would be prudent for all men to exercise their pelvic floor muscles to maintain normal pelvic floor function and start prior to surgery.

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.

Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Erectile function post robotic radical prostatectomy: technical tips to improve outcomes?

Robotic surgery is becoming more and more commonplace. At the same time, so are complications, especially related to erectile function. The population being diagnosed with cancer is younger, with more aggressive cancers and higher expectations for good erectile function postoperatively. We conduct a retrospective analysis of literature over 20 years for Embase and Medline. Search terms used include (Robotic) AND (prostatectomy) AND (erectile function). There are a variety of multifactorial causes, resulting in worsening ED post-robotic radical prostatectomy; however, there are a number of treatments that can support this. There is much we can do to help prevent patients getting postoperative erectile dysfunction post-radical surgery. However, part of this is management of realistic patient expectations.

Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer.

Angiogenesis is required for tumour growth and is induced principally by vascular endothelial growth factor A (VEGF-A). VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer (PCa). In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by serine-arginine protein kinase 1 (SRPK1). Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared with benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in PCa may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knockdown (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small-molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC-3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of PCa. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies for the use of SRPK1 inhibition as a potential anti-angiogenic therapy in PCa.

Pathological analysis of lymph nodes in anterior prostatic fat excised at robot-assisted radical prostatectomy.

AIMS: To assess the lymph node content of anterior prostatic fat (APF) sent routinely at robot-assisted laparoscopic radical prostatectomy (RALP) and the incidence of positive nodes in the extended pelvic lymph node dissection. METHODS: Between September 2008 and April 2012, APF excised from 282 patients who underwent RALP was sent for pathological analysis. This tissue was completely embedded and lymph nodes counted. RESULTS: In total, 49/282 (17%) patients had lymph nodes in the APF, median lymph node yield in this tissue was 1 (range 1­5). In four patients, the lymph nodes contained metastatic deposits. These patients did not have positive nodes elsewhere in the extended lymph node dissection. CONCLUSIONS: APF contains lymph nodes in 1 in 6 patients and infrequently these may be malignant. APF should always be removed at radical prostatectomy. APF should be routinely sent for pathological analysis.

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.

Ketamine-associated lower urinary tract destruction: a new radiological challenge.

AIM: Ketamine is a short-acting dissociative anaesthetic whose hallucinogenic side effects have led to an increase in its illicit use amongst club and party goers. There is a general misconception amongst users that it is a safe drug with few long term side effects, however ketamine abuse is associated with severe urinary tract dysfunction. Presenting symptoms include urinary frequency, nocturia, dysuria, haematuria and incontinence. MATERIALS AND METHODS: We describe the radiological findings found in a series of 23 patients, all with a history of ketamine abuse, who presented with severe lower urinary tract symptoms (LUTS). Imaging techniques used included ultrasonography (US), intravenous urography (IVU), and computed tomography (CT). These examinations were reviewed to identify common imaging findings. All patients with positive imaging findings had also undergone cystoscopy and bladder wall biopsies, which confirmed the diagnosis. The patients in this series have consented to the use of their data in the ongoing research into ketamine-induced bladder pathology. RESULTS: Ultrasound demonstrated small bladder volume and wall thickening. CT revealed marked, generalized bladder wall thickening, mucosal enhancement, and perivesical inflammation. Ureteric wall thickening and enhancement were also observed. In advanced cases ureteric narrowing and strictures were identified using both CT and IVU. Correlation of clinical history, radiological and pathological findings was performed to confirm the diagnosis. CONCLUSION: This case series illustrates the harmful effects of ketamine on the urinary tract and the associated radiological findings. Delayed diagnosis can result in irreversible renal tract damage requiring surgical intervention. It is important that radiologists are aware of this emerging clinical entity as early diagnosis and treatment are essential for successful management.

A systematic review of the role of imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence.

A substantial proportion of patients who have undergone a radical prostatectomy for localised prostate cancer will have either persistently detectable prostate-specific antigen (PSA) levels or a delayed rise in PSA. The optimum treatment for these situations is not known. The key question is whether the PSA is reflective of local or distant progression. For salvage radiotherapy to be most effective, treatment should be considered before the PSA level is allowed to rise too high, when disease is more likely to be confined to the prostate bed. However, at low PSA levels, current imaging techniques are poor at detecting disease, making it difficult to differentiate local and distant recurrences and to target the radiotherapy appropriately. We review current and investigational imaging techniques, including bone scan, computed tomography, magnetic resonance imaging, positron emission tomography and Prostascint, assessing their utility in the situation of biochemical recurrence after radical prostatectomy.

Clinical presentation and initial management of black men and white men with prostate cancer in the United Kingdom: the PROCESS cohort study.

BACKGROUND: In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status. METHODS: This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received. RESULTS: At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15-1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05-1.80). The Delphi analysis did not suggest differential management by ethnicity. CONCLUSIONS: This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.

Pathways to diagnosis for Black men and White men found to have prostate cancer: the PROCESS cohort study.

Black men in England have three times the age-adjusted incidence of diagnosed prostate cancer as compared with their White counterparts. This population-based retrospective cohort study is the first UK-based investigation of whether access to diagnostic services underlies the association between race and prostate cancer. Prostate cancer was ascertained using multiple sources including hospital records. Race and factors that may influence prostate cancer diagnosis were assessed by questionnaire and hospital records review. We found that Black men were diagnosed an average of 5.1 years younger as compared with White men (P<0.001). Men of both races were comparable in their knowledge of prostate cancer, in the delays reported before presentation, and in their experience of co-morbidity and symptoms. Black men were more likely to be referred for diagnostic investigation by a hospital department (P=0.013), although general practitioners referred the large majority of men. Prostate-specific antigen levels were comparable at diagnosis, although Black men had higher levels when compared with same-age White men (P<0.001). In conclusion, we found no evidence of Black men having poorer access to diagnostic services. Differences in the run-up to diagnosis are modest and seem insufficient to explain the higher rate of prostate cancer diagnosis in Black men.

The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice.

Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGFxxxb, where xxx is the amino acid number. The most studied isoforms, VEGF165 and VEGF165b have been shown to be present in tumour and normal tissues respectively. VEGF165b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF165b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF165b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF165b can inhibit growth of multiple tumour types in vivo indicating that VEGF165b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF165b expression by regulation of splicing, overexpression of VEGF165b, or therapeutic delivery of VEGF165b to tumours.