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Importance: Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer. Objectives: To compare recovery and morbidity after robot-assisted radical cystectomy with intracorporeal reconstruction vs open radical cystectomy. Design, Setting, and Participants: Randomized clinical trial of patients with nonmetastatic bladder cancer recruited at 9 sites in the UK, from March 2017-March 2020. Follow-up was conducted at 90 days, 6 months, and 12 months, with final follow-up on September 23, 2021. Interventions: Participants were randomized to receive robot-assisted radical cystectomy with intracorporeal reconstruction (n = 169) or open radical cystectomy (n = 169). Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital within 90 days of surgery. There were 20 secondary outcomes, including complications, quality of life, disability, stamina, activity levels, and survival. Analyses were adjusted for the type of diversion and center. Results: Among 338 randomized participants, 317 underwent radical cystectomy (mean age, 69 years; 67 women [21%]; 107 [34%] received neoadjuvant chemotherapy; 282 [89%] underwent ileal conduit reconstruction); the primary outcome was analyzed in 305 (96%). The median number of days alive and out of the hospital within 90 days of surgery was 82 (IQR, 76-84) for patients undergoing robotic surgery vs 80 (IQR, 72-83) for open surgery (adjusted difference, 2.2 days [95% CI, 0.50-3.85]; P = .01). Thromboembolic complications (1.9% vs 8.3%; difference, -6.5% [95% CI, -11.4% to -1.4%]) and wound complications (5.6% vs 16.0%; difference, -11.7% [95% CI, -18.6% to -4.6%]) were less common with robotic surgery than open surgery. Participants undergoing open surgery reported worse quality of life vs robotic surgery at 5 weeks (difference in mean European Quality of Life 5-Dimension, 5-Level instrument scores, -0.07 [95% CI, -0.11 to -0.03]; P = .003) and greater disability at 5 weeks (difference in World Health Organization Disability Assessment Schedule 2.0 scores, 0.48 [95% CI, 0.15-0.73]; P = .003) and at 12 weeks (difference in WHODAS 2.0 scores, 0.38 [95% CI, 0.09-0.68]; P = .01); the differences were not significant after 12 weeks. There were no statistically significant differences in cancer recurrence (29/161 [18%] vs 25/156 [16%] after robotic and open surgery, respectively) and overall mortality (23/161 [14.3%] vs 23/156 [14.7%]), respectively) at median follow-up of 18.4 months (IQR, 12.8-21.1). Conclusions and Relevance: Among patients with nonmetastatic bladder cancer undergoing radical cystectomy, treatment with robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy resulted in a statistically significant increase in days alive and out of the hospital over 90 days. However, the clinical importance of these findings remains uncertain. Trial Registration: ISRCTN Identifier: ISRCTN13680280; ClinicalTrials.gov Identifier: NCT03049410.
Subject(s)
Cystectomy , Robotic Surgical Procedures , Robotics , Urinary Bladder Neoplasms , Urinary Diversion , Aged , Cystectomy/adverse effects , Cystectomy/methods , Cystectomy/mortality , Female , Humans , Male , Morbidity , Neoplasm Recurrence, Local , Postoperative Complications/etiology , Quality of Life , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods , Robotic Surgical Procedures/mortality , Treatment Outcome , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery , Urinary Diversion/adverse effects , Urinary Diversion/methods , Urinary Diversion/mortalityABSTRACT
OBJECTIVES: To compare trends in the use of robot-assisted radical cystectomy (RARC) and changes over time in peri-operative outcomes in selected North American and European centres. MATERIALS AND METHODS: We conducted a retrospective evaluation of 2401 patients treated with open radical cystectomy (ORC) or RARC for bladder cancer at 12 centres in North America and Europe between 2006 and 2018. We used the Kruskal-Wallis and chi-squared test to evaluate differences between continuous and categorical variables. RESULTS: Overall, 49.5% of patients underwent RARC and 51.5% ORC. RARC became the most commonly performed procedure in contemporary patients, with an increase from 29% in 2006-2008 to 54% in 2015-2018 (P < 0.001). In the North American centres the use of RARC was higher than that of ORC from 2006, and remained stable over time, whereas in the European centres its use increased exponentially from 2% to 50%. In both groups patients who underwent RARC had less advanced T stages (P < 0.001), lower American Society of Anesthesiologists scores (P < 0.05), lower blood loss (P = 0.001) and shorter length of hospital stay (P < 0.05). No differences were found in early complications. Early readmission and re-operation rates were worse for patients treated with RARC in the European centres; however, when contemporary patients only were considered, the statistical significance was lost. CONCLUSION: The present study shows that the use of RARC has constantly increased since its introduction, overtaking ORC in the most contemporary series. While RARC was more frequently performed than ORC since its introduction in the North American centres and its use remained substantially stable over time, its use increased exponentially in the European centres. The different trends in use of RARC/ORC and changes over time in peri-operative outcomes between the North American and European centres can be attributed to the earlier introduction and spread of RARC in the former compared with the latter.
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OBJECTIVES: To perform a cost analysis comparing the cost of robot-assisted radical cystectomy (RARC) with open RC (ORC) in a UK tertiary referral centre and to identify the key cost drivers. PATIENTS AND METHODS: Data on hospital length of stay (LOS), operative time (OT), transfusion rate, and volume and complication rate were obtained from a prospectively updated institutional database for patients undergoing RARC or ORC. A cost decision tree model was created. Sensitivity analysis was performed to find key drivers of overall cost and to find breakeven points with ORC. Monte Carlo analysis was performed to quantify the variability in the dataset. RESULTS: One RARC procedure costs £12 449.87, or £12 106.12 if the robot was donated via charitable funds. In comparison, one ORC procedure costs £10 474.54. RARC is 18.9% more expensive than ORC. The key cost drivers were OT, LOS, and the number of cases performed per annum. CONCLUSION: High ongoing equipment costs remain a large barrier to the cost of RARC falling. However, minimal improvements in patient quality of life would be required to offset this difference.
Subject(s)
Cystectomy/economics , Health Care Costs/statistics & numerical data , Postoperative Complications/economics , Robotic Surgical Procedures/economics , Adolescent , Adult , Aged , Aged, 80 and over , Blood Transfusion/economics , Costs and Cost Analysis , Cystectomy/adverse effects , Cystectomy/methods , Decision Trees , Female , Humans , Length of Stay/economics , Male , Middle Aged , Operating Rooms/economics , Operative Time , Quality-Adjusted Life Years , Robotic Surgical Procedures/adverse effects , Tertiary Care Centers/economics , United Kingdom , Young AdultABSTRACT
PURPOSE: To explore the views and experiences of health care professionals (HCPs), men diagnosed with localised prostate cancer and their partners about the provision of advice on diet and physical activity after diagnosis and treatment for localised prostate cancer. METHODS: Semi-structured in-depth interviews with ten HCPs (Consultant Urological Surgeons, Uro-Oncology Clinical Nurse Specialists and Allied Health Professionals: see Table 1) and sixteen men diagnosed with localised prostate cancer and seven of their partners. Data from interviews were thematically analysed using the Framework Approach. RESULTS: The men and their partners provided differing accounts to the HCPs and sometimes to each other concerning the provision of advice on diet and physical activity. Some men were unable to recall receiving such advice from HCPs. Factors impacting upon advice-giving included the perceived lack of an evidence base to support dietary and physical activity advice and the credibility of advice providers. The timing of advice provision was a contentious issue as some HCPs believed that patients might not be willing to receive dietary and physical activity advice at the time of diagnosis, whilst others viewed this an opportune time to provide behaviour change information. Patients concurred with the latter opinion. CONCLUSIONS: Men and their partners would value nutritional and physical activity advice from their HCP, after a localised prostate cancer diagnosis. Men would prefer to receive this advice at an early stage in their cancer journey and may implement behaviour change if the received advice is clear and evidence-based. HCPs should receive suitable training regarding what information to provide to men and how best to deliver this information.
Subject(s)
Diet , Exercise , Health Behavior , Life Style , Prostatic Neoplasms/therapy , Female , Health Personnel , Humans , Male , Middle Aged , Perception , Prostatic Neoplasms/diagnosis , Qualitative ResearchABSTRACT
BACKGROUND: The experience and acceptability of lifestyle interventions for men with localised prostate cancer are not well understood, yet lifestyle interventions are increasingly promoted for cancer survivors. We explored the opinions, experiences and perceived acceptability of taking part in nutritional and physical activity interventions amongst men with prostate cancer and their partners; with the ultimate plan to use such information to inform the development of nutritional and physical activity interventions for men with prostate cancer. METHODS: Semi-structured interviews with 16 men, and seven partners, undergoing curative surgery or radiotherapy for prostate cancer. Interviews explored experiences of lifestyle interventions, acceptable changes participants would make and perceived barriers and facilitators to change. Interviews were thematically analysed using the framework approach. RESULTS: Men were frequently open to lifestyle modification and family support was considered vital to facilitate change. Health beneficial, clinician endorsed, understandable, enjoyable interventions were perceived as attractive. Barriers included 'modern' digital technology, poor weather, competing commitments or physical limitations, most notably incontinence following radical prostatectomy. Men were keen to participate in research, with few negative aspects identified. CONCLUSIONS: Men are willing to change behaviour but this needs to be supported by clinicians and health professionals facilitating lifestyle change. An 'intention-behaviour gap', when an intended behaviour does not materialise, may exist. Digital technology for data collection and lifestyle measurement may not be suitable for all, and post-surgery urinary incontinence is a barrier to physical activity. These novel findings should be incorporated into lifestyle intervention development, and implemented clinically.
Subject(s)
Diet Therapy/psychology , Exercise/psychology , Patient Acceptance of Health Care/psychology , Prostatectomy/trends , Prostatic Neoplasms/psychology , Risk Reduction Behavior , Aged , Attitude to Health , Exercise/physiology , Humans , Male , Middle Aged , Motivation , Prostatectomy/adverse effects , Prostatic Neoplasms/therapy , Qualitative Research , Radiotherapy/adverse effects , Radiotherapy/trendsABSTRACT
BACKGROUND: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes. METHODS: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015). RESULTS: Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis. CONCLUSIONS: UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials.
Subject(s)
Prostatic Neoplasms/mortality , Aged , Cause of Death , Death Certificates , Humans , Male , Prostate/pathology , Prostatic Neoplasms/pathology , Sensitivity and SpecificityABSTRACT
OBJECTIVES: To assess the impact of the introduction of robot-assisted radical cystectomy (RARC) on an established enhanced recovery programme (ERP) and to examine the effect on mortality and morbidity rates, transfusion rates, and length of stay (LOS). PATIENTS AND METHODS: Data on 102 consecutive patients undergoing RARC with full intracorporeal reconstruction were obtained from our prospectively updated institutional database. These data were compared to previously published retrospective results from three separate groups of patients undergoing open radical cystectomy (ORC) at our centre. Our primary focus was perioperative outcomes including transfusion rate, complication rates, 30- and 90-day mortality rates, and LOS. RESULTS: The demographics of the comparative groups showed no significant difference in age, gender distribution, and American Society of Anesthesiologists grade. A significant reduction in transfusion rate was seen in RARC vs ORC (P < 0.001). The median LOS for the RARC group was 8 vs 13 days for the ORC group (P < 0.001). There was trend to a lower total complication rate (48% vs 31%). The 30- and 90-day mortality rates were equivalent between the groups (2%). CONCLUSIONS: Introduction of RARC and intracorporeal reconstruction represents the single biggest impact on our ERP, with significant reduction in transfusion rates and LOS, and a trend towards a lower complication rate.
Subject(s)
Cystectomy , Robotic Surgical Procedures , Urinary Bladder Neoplasms/surgery , Urinary Diversion , Adolescent , Adult , Aged , Aged, 80 and over , Cystectomy/adverse effects , Cystectomy/methods , Cystectomy/statistics & numerical data , Female , Humans , Male , Middle Aged , Postoperative Complications , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods , Robotic Surgical Procedures/statistics & numerical data , Urinary Bladder/surgery , Urinary Bladder Neoplasms/epidemiology , Urinary Diversion/adverse effects , Urinary Diversion/methods , Urinary Diversion/statistics & numerical data , Young AdultABSTRACT
Objective: The aim of this study was to investigate whether pre-operative comorbidity status measured by the Charlson comorbidity index (CCI) or cardiopulmonary exercise testing (CPET) is associated with postoperative complications and length of stay (LOS) in patients undergoing robot-assisted radical cystectomy and intracorporeal urinary diversion (RARC-ICUD). Patients and methods: We conducted a retrospective study of a prospectively maintained database of 428 consecutive patients who underwent RARC-ICUD at a tertiary referral centre between 2011 and 2019. CCI was correlated with peri-operative outcomes including postoperative LOS, Clavien-Dindo (CD) complications and survival. A planned subgroup analysis was performed to evaluate the relationship between pre-operative CPET, and the same outcomes utilising the threshold of anaerobic threshold (AT) ≥ 11/ <11 ml/kg/min were analysed. Results: Of the total cohort, 350 patients undergoing RARC-ICUD with complete data were included in the final analysis. A CCI score ≥5 was associated with a higher rate of CD III-V complications at 30-day incidence rate ratio (IRR) = 3.033, (p = 0.02) and at 90-day IRR 2.495, (p = 0.04) postsurgery. LOS was not associated with CCI; the strongest association with LOS was a CD complication of any grading. CCI did not predict readmission or mortality rates after surgery. Subanalyses of patients who underwent pre-operative CPET found that CPET <11 ml/kg/min did not predict for LOS, CD complications or death within 1 year of surgery. Conclusions: CCI score is a simple, reliable and cost-effective way of identifying patients at increased risk of complication after RARC-ICUD. Surgeons performing radical cystectomy should consider utilising CCI to augment pre-operative patient counselling prior to RARC-ICUD.
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AIMS: To examine associations between the transcription factors CCCTC-binding factor (CTCF) and forkhead box protein A1 (FOXA1) and the androgen receptor (AR) and their association with components of the insulin-like growth factor (IGF)-pathway in a cohort of men with localized prostate cancer. METHODS: Using prostate tissue samples collected during the Prostate cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) trial (N = 70 to 92, depending on section availability), we assessed the abundance of CTCF, FOXA1, AR, IGFIR, p-mTOR, PTEN and IGFBP-2 proteins using a modified version of the Allred scoring system. Validation studies were performed using large, publicly available datasets (TCGA) (N = 489). RESULTS: We identified a strong correlation between CTCF and AR staining with benign prostate tissue. CTCF also strongly associated with the IGFIR, with PTEN and with phospho-mTOR. FOXA1 was also correlated with staining for the IGF-IR, with IGFBP-2 and with staining for activated phosphor-mTOR. The staining for the IGF-IR was strongly correlated with the AR. CONCLUSION: Our findings emphasise the close and complex links between the endocrine controls, well known to play an important role in prostate cancer, and the transcription factors implicated by the recent genetic evidence.
Subject(s)
Prostatic Neoplasms , Somatomedins , Male , Humans , Androgens , Insulin-Like Growth Factor Binding Protein 2/genetics , CCCTC-Binding Factor/genetics , Cell Line, Tumor , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Somatomedins/genetics , Somatomedins/metabolism , TOR Serine-Threonine Kinases/metabolism , Insulin-Like Growth Factor I/metabolism , Hepatocyte Nuclear Factor 3-alpha/genetics , Hepatocyte Nuclear Factor 3-alpha/metabolismABSTRACT
OBJECTIVES: Interventions designed to improve men's diet and physical activity (PA) have been recommended as methods of cancer prevention. However, little is known about specific factors that support men's adherence to these health behaviour changes, which could inform theory-led diet and PA interventions. We aimed to explore these factors in men following prostatectomy for prostate cancer (PCa). DESIGN, SETTING AND PARTICIPANTS: A qualitative study using semistructured interviews with men, who made changes to their diet and/or PA as part of a factorial randomised controlled trial conducted at a single hospital in South West England. Participants were 17 men aged 66 years, diagnosed with localised PCa and underwent prostatectomy. Interview transcripts underwent thematic analysis. RESULTS: Men were ambivalent about the relationship of nutrition and PA with PCa risk. They believed their diet and level of PA were reasonable before being randomised to their interventions. Men identified several barriers and facilitators to performing these new behaviours. Barriers included tolerance to dietary changes, PA limitations and external obstacles. Facilitators included partner involvement in diet, habit formation and brisk walking as an individual activity. Men discussed positive effects associated with brisk walking, such as feeling healthier, but not with nutrition interventions. CONCLUSIONS: The facilitators to behaviour change suggest that adherence to trial interventions can be supported using well-established behaviour change models. Future studies may benefit from theory-based interventions to support adherence to diet and PA behaviour changes in men diagnosed with PCa.
Subject(s)
Prostatectomy , Prostatic Neoplasms , Exercise , Humans , Male , Nutritional Status , Prostatic Neoplasms/diagnosis , Qualitative ResearchABSTRACT
BACKGROUND: Evidence from observational studies have shown that moderate intensity physical activity can reduce risk of progression and cancer-specific mortality in participants with prostate cancer. Epidemiological studies have also shown participants taking metformin to have a reduced risk of prostate cancer. However, data from randomised controlled trials supporting the use of these interventions are limited. The Prostate cancer-Exercise and Metformin Trial examines that feasibility of randomising participants diagnosed with localised or locally advanced prostate cancer to interventions that modify physical activity and blood glucose levels. The primary outcomes are randomisation rates and adherence to the interventions over 6 months. The secondary outcomes include intervention tolerability and retention rates, measures of insulin-like growth factor I, prostate-specific antigen, physical activity, symptom-reporting, and quality of life. METHODS: Participants are randomised in a 2 × 2 factorial design to both a physical activity (brisk walking or control) and a pharmacological (metformin or control) intervention. Participants perform the interventions for 6 months with final measures collected at 12 months follow-up. DISCUSSION: Our trial will determine whether participants diagnosed with localised or locally advanced prostate cancer, who are scheduled for radical treatments or being monitored for signs of cancer progression, can be randomised to a 6 months physical activity and metformin intervention. The findings from our trial will inform a larger trial powered to examine the clinical benefits of these interventions. TRIAL REGISTRATION: Prostate Cancer Exercise and Metformin Trial (Pre-EMpT) is registered on the ISRCTN registry, reference number ISRCTN13543667 . Date of registration 2nd August 2018-retrospectively registered. First participant was recruited on 11th September 2018.
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INTRODUCTION: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle-invasive bladder cancer. However, response rates and survival remain suboptimal. We evaluated the efficacy, safety, and tolerability of cisplatin plus cabazitaxel. METHODS: A phase II single-arm trial was designed to recruit at least 26 evaluable patients. This would give 80% power to detect the primary endpoint, an objective response rate defined as a pathologic complete response plus partial response (pathologic downstaging), measured by pathologic staging at cystectomy (p0 = 0.35 and p1 = 0.60, α = 0.05). RESULTS: Objective response was seen in 15 of 26 evaluable patients (57.7%) and more than one- third of patients achieved a pathologic complete response (9/26; 34.6%). Seventy-eight percent of the patients (21/27) completed all cycles of treatment, with only 6.7% of the reported adverse events being graded 3 or 4. There were 6 treatment-related serious adverse event reported, but no suspected unexpected serious adverse reactions. In the patients who achieved an objective response, the median progression-free survival and overall survival were not reached (median follow-up of 41.5 months). In contrast, the median progression-free survival (7.2 months) and overall survival (16.9 months) were significantly worse (P = .001, log-rank) in patients who did not achieve an objective response. CONCLUSION: Cabazitaxel plus cisplatin for neoadjuvant treatment of muscle-invasive bladder cancer can be considered a well-tolerated and effective regimen before definitive therapy with higher rates (57.7%) of objective response, comparing favorably to that with of cisplatin/gemcitabine (23%-26%). These results warrant further evaluation in a phase III study.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/surgery , Chemotherapy, Adjuvant , Cisplatin/adverse effects , Cystectomy , Disease-Free Survival , Humans , Muscles , Neoadjuvant Therapy , Taxoids , Treatment Outcome , Urinary Bladder , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/surgeryABSTRACT
Prostate cancer is the second major cause of male cancer deaths. Obesity, type 2 diabetes, and cancer risk are linked. Insulin-like growth factor II (IGF-II) is involved in numerous cellular events, including proliferation and survival. The IGF-II gene shares its locus with the lncRNA, H19. IGF-II/H19 was the first gene to be identified as being "imprinted"-where the paternal copy is not transcribed-a silencing phenomenon lost in many cancer types. We disrupted imprinting behaviour in vitro by altering metabolic conditions and quantified it using RFLP, qPCR and pyrosequencing; changes to peptide were measured using RIA. Prostate tissue samples were analysed using ddPCR, pyrosequencing and IHC. We compared with in silico data, provided by TGCA on the cBIO Portal. We observed disruption of imprinting behaviour, in vitro, with a significant increase in IGF-II and a reciprocal decrease in H19 mRNA; the increased mRNA was not translated into peptides. In vivo, most specimens retained imprinting status apart from a small subset which showed reduced imprinting. A positive correlation was seen between IGF-II and H19 mRNA expression, which concurred with findings of larger Cancer Genome Atlas (TGCA) cohorts. This positive correlation did not affect IGF-II peptide. Our findings show that type 2 diabetes and/or obesity, can directly affect regulation growth factors involved in carcinogenesis, indirectly suggesting a modification of lifestyle habits may reduce cancer risk.
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Androgen deprivation treatment in prostate cancer patients is well established; however, resistance to such treatment manifests itself by progression to castration-resistant prostate cancer (CRPC). Despite significant advances in treatment options for patients with CRPC, their prognosis remains poor. Resistance results from multiple processes that facilitate cancer cell growth and survival. Mechanisms underlying the shift to castrate resistance have been attributed to a complex interplay of clonal selection, reactivation of the androgen receptor axis despite castrate levels of serum testosterone, stress-induced prosurvival genes and cytoprotective chaperone networks and alternative mitogenic growth factor pathways. This article discusses several pathways involved in the development of CRPC, with a particular focus on those mechanisms that have led to the development of new targeted therapies.
Subject(s)
Prostatic Neoplasms/therapy , Androgen Antagonists/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/prevention & control , Bone Neoplasms/secondary , Humans , Immunotherapy, Active , Male , Molecular Chaperones/biosynthesis , Molecular Targeted Therapy , Neovascularization, Pathologic , Orchiectomy , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/pathology , Testosterone/blood , Treatment FailureABSTRACT
Localized prostate cancer (PCa) is a manageable disease but for most men with metastatic disease, it is often fatal. A western diet has been linked with PCa progression and hyperglycaemia has been associated with the risk of lethal and fatal prostate cancer. Using PCa cell lines, we examined the impact of IGF-I and glucose on markers of epithelial-to-mesenchymal transition (EMT), migration and invasion. We examined the underlying mechanisms using cell lines and tumour tissue samples. IGF-I had differential effects on the process of EMT: inhibiting in normal and promoting in cancer cells, whereas hyperglycamia alone had a stimulatory effect in both. These effects were independent of IGF and in both cases, hyperglycaemia induced an increase IGFBP-2(tumour promoter) and FOXA1. A positive correlation existed between levels of IGFBP-2 and FOXA1 in benign and cancerous prostate tissue samples and in vitro and in vivo data indicated that FOXA1 strongly interacted with the IGFBP-2 gene in normal prostate epithelial cells that was associated with a negative regulation of IGFBP-2, whereas in cancer cells the level of FOXA1 associating with the IGFBP-2 gene was minimal, suggesting loss of this negative regulation. IGF-I and hyperglycaemia-induced FOXA1/IGFBP-2 play important roles in EMT.
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There are mixed reports on the role that IGFBP-2 plays in cancer progression, with some indicating a tumour suppressive role and others showing that IGFBP-2 may act as an oncogene. These apparent contradictions may be context and tissue specific. In this study we determined the role that IGFBP-2 played on the phenotype and chemosensitivity of a selection of bladder cancer cell lines and investigated how the abundance of IGFBP-2 was regulated. We found that IGFBP-2 was more abundant in the epithelial bladder cancer cells, RT4 and UMUC3 and absent in the more mesenchymal T24 and TCCSUP cells. Silencing IGFBP-2 using siRNA in epithelial RT4 cells promoted cell proliferation, invasion, colony formation, resulted in a reduction in epithelial (E-cadherin) and an increase in mesenchymal (N-cadherin) markers and increased sensitivity to cisplatin-induced cell death. Conversely, we observed the opposite effects when adding exogenous IGFBP-2 to the mesenchymal T24 cells. We determined that IGFBP-2 was epigenetically silenced via DNA methylation as the cells adopted a mesenchymal phenotype. Collectively these data suggest that IGFBP-2 acts as a tumour suppressor and marker of chemosensitivity in epithelial bladder cancer cells and that IGFBP-2 is epigenetically silenced by methylation to promote bladder cancer progression.
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OBJECTIVE: Dietary factors and physical activity may alter prostate cancer progression. We explored the feasibility of lifestyle interventions following radical prostatectomy for localised prostate cancer. DESIGN: Patients were recruited into a presurgical observational cohort; following radical prostatectomy, they were offered randomisation into a 2×3 factorial randomised controlled trial (RCT). SETTING: A single National Health Service trust in the South West of England, UK. PARTICIPANTS: Those with localised prostate cancer and listed for radical prostatectomy were invited to participate. RANDOMISATION: Random allocation was performed by the Bristol Randomised Trial Collaboration via an online system. INTERVENTIONS: Men were randomised into both a modified nutrition group (either increased vegetable and fruit, and reduced dairy milk; or lycopene supplementation; or control) and a physical activity group (brisk walking or control) for 6 months. BLINDING: Only the trial statistician was blind to allocations. PRIMARY OUTCOME MEASURES: Primary outcomes were measures of feasibility: randomisation rates and intervention adherence at 6 months. Collected at trial baseline, three and six months, with daily adherence reported throughout. Our intended adherence rate was 75% or above, the threshold for acceptable adherence was 90%. RESULTS: 108 men entered the presurgical cohort, and 81 were randomised into the postsurgical RCT (randomisation rate: 93.1%) and 75 completed the trial. Of 25 men in the nutrition intervention, 10 (40.0%; 95% CI 23.4% to 59.3%) adhered to the fruit and vegetable recommendations and 18 (72.0%; 95% CI 52.4% to 85.7%) to reduced dairy intake. Adherence to lycopene (n=28), was 78.6% (95% CI 60.5% to 89.8%), while 21/39 adhered to the walking intervention (53.8%; 95% CI 38.6% to 68.4%). Most men were followed up at 6 months (75/81; 92.6%). Three 'possibly related' adverse events were indigestion, abdominal bloating and knee pain. CONCLUSIONS: Interventions were deemed feasible, with high randomisation rates and generally good adherence. A definitive RCT is proposed. TRIAL REGISTRATION NUMBER: ISRCTN 99048944.
Subject(s)
Diet, Healthy/methods , Exercise Therapy/methods , Exercise , Prostatectomy/rehabilitation , Prostatic Neoplasms/rehabilitation , Diet , England , Feasibility Studies , Fruit , Humans , Male , Middle Aged , Nutritional Status , Prostatic Neoplasms/surgery , VegetablesABSTRACT
BACKGROUND: To assess the differential effect of robotic assisted radical cystectomy (RARC) versus open radical cystectomy (ORC) on survival outcomes in matched analyses performed on a large multicentric cohort. METHODS: The study included 9757 patients with urothelial bladder cancer (BCa) treated in a consecutive manner at each of 25 institutions. All patients underwent radical cystectomy with bilateral pelvic lymphadenectomy. To adjust for potential selection bias, propensity score matching 2:1 was performed with two ORC patients matched to one RARC patient. The propensity-matched cohort included 1374 patients. Multivariable competing risk analyses accounting for death of other causes, tested association of surgical technique with recurrence and cancer specific mortality (CSM), before and after propensity score matching. RESULTS: Overall, 767 (7.8%) patients underwent RARC and 8990 (92.2%) ORC. The median follow-up before and after propensity matching was 81 and 102 months, respectively. In the overall population, the 3-year recurrence rates and CSM were 37% vs. 26% and 34% vs. 24% for ORC vs. RARC (all p values > 0.1), respectively. On multivariable Cox regression analyses, RARC and ORC had similar recurrence and CSM rates before and after matching (all p values > 0.1). CONCLUSIONS: Patients treated with RARC and ORC have similar survival outcomes. This data is helpful in consulting patients until long term survival outcomes of level one evidence is available.
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INTRODUCTION: The use of robotic-assisted radical cystectomy (RARC) is becoming more widespread. While its safety is accepted, its oncological efficacy as compared to the current standard, open radical cystectomy (ORC), remains debatable. MATERIALS AND METHODS: The aim of this study is to compare the rates of positive soft tissue surgical margins (STSM), between patients treated with RARC or ORC, using a large contemporaneous collaborative database. We included 2,536 patients with urothelial carcinoma of the bladder treated at 26 institutions. A propensity-score matching 1:1 was performed with 3 ORC patients matched to 1 RARC patient. The final cohort included 1,614 patients. Uni- and multivariable logistic regression analyses tested the impact of surgical technique on STSM status, before and after propensity-score matching. RESULTS: Overall, 870 (34%) patients underwent RARC and 1,666 (66%) ORC. The overall STSM rate was 11%; 10% in the ORC group and 13% in the RARC group. Within the propensity-score-matched cohort, the positive STSM rate were 14% and 13% in the ORC and RARC group, respectively (P = 0.1). In multivariable analysis, after propensity match RARC approach was not associated with the risk of a positive STSM (P = 0.1). These results were confirmed in the subgroup of patients with pathologic non-organ-confined or organ-confined diseases. CONCLUSIONS: While treatment with RARC is associated with a higher absolute rate of STSM, the difference did not remain after adjustment for the effects of other established prognostic factors. Results from ongoing trials are awaited to assess the validity of these findings.
Subject(s)
Carcinoma, Transitional Cell/therapy , Cystectomy/methods , Margins of Excision , Robotic Surgical Procedures/methods , Urinary Bladder Neoplasms/therapy , Aged , Carcinoma, Transitional Cell/pathology , Chemotherapy, Adjuvant , Cystectomy/adverse effects , Female , Follow-Up Studies , Humans , Length of Stay , Lymph Node Excision , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Propensity Score , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Treatment Outcome , Urinary Bladder/pathology , Urinary Bladder/surgery , Urinary Bladder Neoplasms/pathologyABSTRACT
OBJECTIVES: To evaluate the recent developments in robotic urological surgery, as the introduction of robotic technology has overcome many of the difficulties of pure laparoscopic surgery enabling surgeons to perform complex minimally invasive procedures with a shorter learning curve. Robot-assisted surgery (RAS) is now offered as the standard for various surgical procedures across multiple specialities. METHODS: A systematic search of MEDLINE, PubMed and EMBASE databases was performed to identify studies evaluating robot-assisted simple prostatectomy, salvage radical prostatectomy, surgery for urolithiasis, distal ureteric reconstruction, retroperitoneal lymph node dissection, augmentation ileocystoplasty, and artificial urinary sphincter insertion. Article titles, abstracts, and full text manuscripts were screened to identify relevant studies, which then underwent data extraction and analysis. RESULTS: In all, 72 studies evaluating the above techniques were identified. Almost all studies were retrospective single-arm case series. RAS appears to be associated with reduced morbidity, less blood loss, reduced length of stay, and comparable clinical outcomes in comparison to the corresponding open procedures, whilst having a shorter operative duration and learning curve compared to the equivalent laparoscopic techniques. CONCLUSION: Emerging data demonstrate that the breadth and complexity of urological procedures performed using the da Vinci® platform (Intuitive Surgical Inc., Sunnyvale, CA, USA) is continually expanding. There is a gaining consensus that RAS is producing promising surgical results in a wide range of procedures. A major limitation of the current literature is the sparsity of comparative trials evaluating these procedures.