Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial.

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.

Expert Elicitation to Inform a Cost-Effectiveness Analysis of Screening for Renal Cancer.

BACKGROUND: Population screening for renal cell carcinoma (RCC) using ultrasound has the potential to improve survival outcomes; however, a cost-effectiveness analysis (CEA) has yet to be performed. Owing to the lack of existing evidence, we performed structured expert elicitation to derive unknown quantities to inform the CEA. OBJECTIVE: To elicit the cancer stage distribution (proportion of individuals with each stage of cancer) for different RCC screening scenarios and the annual transition probabilities for undiagnosed disease becoming diagnosed in the National Health Service. METHODS: The study design and reporting adhered to the Reporting Guidelines for the Use of Expert Judgement in Model-Based Economic Evaluations. The elicitation was conducted face-to-face or via telephone between each individual expert and the facilitator, aided by online material. For multinomial data, Connor-Mosimann and modified Connor-Mosimann distributions were fitted for each expert and for all experts combined using mathematical linear pooling. RESULTS: A total of 24 clinical experts were invited, and 71% participated (7 urologists, 6 oncologists, 4 radiologists). The modified Connor-Mosimann distribution provided the best fit for most elicited quantities. Greater uncertainty was noted for the elicited transition probabilities compared with the elicited stage distributions. CONCLUSION: We performed the first expert elicitation of RCC screening parameters, crucial information that will inform the CEA of screening. In addition, the elicited quantities may enable future health economic evaluations assessing the value of diagnostic tools and pathways in RCC.

Targeted augmented reality-guided transperineal prostate biopsies study: initial experience.

Background: Transperineal biopsy of magnetic resonance imaging (MRI)-detected prostate lesions is now the established technique used in prostate cancer (CaP) diagnostics. Virtual Surgery Intelligence (VSI) Holomedicine by Apoqlar (Hamburg, Germany) is a mixed reality (MR)/augmented reality (AR) software platform that runs on the HoloLens II system (Microsoft, Redford, USA). Multiparametric prostate MRI images were converted into 3D holograms and added into a MR space, enabling visualization of a 3D hologram and image-assisted prostate biopsy. Objective: The Targeted Augmented Reality-GuidEd Transperineal (TARGET) study investigated the feasibility of performing AR-guided prostate biopsies in a MR framework, using the VSI platform in patients with MRI-detected prostate lesions. Methods: Ten patients with a clinical suspicion of CaP on MRI (Prostate Imaging-Reporting and Data System, PI-RADS 4/5) were uploaded to the VSI HoloLens system. Two MR/AR-guided prostate biopsies were then acquired using the PrecisionPoint Freehand transperineal biopsy system. Cognitive fusion biopsies were performed as standard of care following the MR/AR-guided prostate biopsies. Results: All 10 patients successfully underwent MR/AR-guided prostate biopsy after 3D MR images were overlaid on the patient's body. Prostatic tissue was obtained in all MR/AR-guided specimens. Seven patients (70%) had matching histology in both the standard and MR/AR-guided biopsies. The remaining three had ISUP (International Society of Urological Pathology) Grade 2 CaP. There were no immediate complications. Conclusion: We believe this is a world first. The initial feasibility data from the TARGET study demonstrated that an MR/AR-guided prostate biopsy utilizing the VSI Holomedicine system is a viable option in CaP diagnostics. The next stage in development is to combine AR images with real-time needle insertion and to provide further data to formally appraise the sensitivity and specificity of the technique.

A practical guide on the non-antibiotic options available in the prevention of recurrent urinary tract infections in women.

Urinary Tract infection (UTI) is one of the most common infections worldwide, patients present to multiple different specialities in the community, primary and secondary care. Antibiotics are considered standard first line therapy in the treatment of urinary tract infections, however there is an alarming rise in global antibiotic resistance rates, so much so that the World Health Organisation has labelled antibiotic resistance as one of the biggest challenges to public health in our lifetime, publishing a global action plan to tackle this challenge. As a result, there is an increasing need to discover non-antibiotic alternatives, recently a number of novel therapies have been introduced into clinical practice. These are divided into oral, topical, intravesical and immunomodulation therapies. The aim of this paper is to summarise the current non-antibiotic treatments as a practical guide to utilise in patient care.

Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder.

BACKGROUND: Meta-analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose-intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway. METHODS: Eighty consecutive patients with MIBC were treated with AMVAC as NAC by 2 UK multidisciplinary uro-oncology teams. Three or 4 cycles of AMVAC (methotrexate 30 mg/m(2) , vinblastine 3 mg/m(2) , doxorubicin 30 mg/m(2) , and cisplatin 70 mg/m(2) ) were given at 2-week intervals, with granulocyte colony-stimulating factor support, prior to either radical surgery or radical radiotherapy. RESULTS: All planned cycles of chemotherapy were completed, without dose reduction or delay in 84% of patients. All 80 patients subsequently received their planned definitive therapy. Grade 3/4 toxicities were seen in 26% of the 42% of patients for whom toxicity data are available, including 12% grade 3/4 neutropenia. Pathological complete response to AMVAC was seen in 43% of 60 surgical patients. Objective radiological local response was seen in 83% of 57 evaluable patients. Two-year disease-free and overall survival were 65% and 77%, respectively. CONCLUSIONS: AMVAC is safe and appears to be a well-tolerated and effective NAC regimen for MIBC. It minimizes delays to definitive treatment and produces excellent pathological and radiological response rates. It is an appropriate comparator for future randomized trials.

Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic.

UNLABELLED: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Haematuria clinics with same day imaging and flexible cystoscopy are an efficient way for investigating patients with haematuria. The principal role of haematuria clinics with reference to bladder cancer is to determine which patients are 'normal' and may be discharged, and which patients are abnormal and should undergo rigid cystoscopy. It is well recognised that CT urography offers a thorough evaluation of the upper urinary tract for stones, renal masses and urothelial neoplasms but the role of CT urography for diagnosing bladder cancer is less certain. The aim of the present study was to evaluate the diagnostic accuracy of CT urography in patients with visible haematuria aged >40 years and to determine if CT urography has a role for diagnosing bladder cancer. This study shows that the optimum diagnostic strategy for investigating patients with visible haematuria aged >40 years with infection excluded is a combined strategy using CT urography and flexible cystoscopy. Patients positive for bladder cancer on CT urography should be referred directly for rigid cystoscopy and so avoid flexible cystoscopy. The number of flexible cystoscopies required therefore may be reduced by 17%. The present study also shows that the diagnostic accuracy of voided urine cytology is too low to justify its continuing use in a haematuria clinic using CT urography and flexible cystoscopy. OBJECTIVES: To evaluate and compare the diagnostic accuracy of computed tomography (CT) urography with flexible cystoscopy and voided urine cytology for diagnosing bladder cancer. To evaluate diagnostic strategies using CT urography as: (i) an additional test or (ii) a replacement test or (iii) a triage test for diagnosing bladder cancer in patients referred to a hospital haematuria rapid diagnosis clinic. PATIENTS AND METHODS: The clinical cohort consisted of a consecutive series of 778 patients referred to a hospital haematuria rapid diagnosis clinic from 1 March 2004 to 17 December 2007. Criteria for referral were at least one episode of macroscopic haematuria, age >40 years and urinary tract infection excluded. Of the 778 patients, there were 747 with technically adequate CT urography and flexible cystoscopy examinations for analysis. On the same day, patients underwent examination by a clinical nurse specialist followed by voided urine cytology, CT urography and flexible cystoscopy. Voided urine cytology was scored using a 5-point system. CT urography was reported immediately by a uroradiologist and flexible cystoscopy performed by a urologist. Both examinations were scored using a 3-point system: 1, normal; 2, equivocal; and 3, positive for bladder cancer. The reference standard consisted of review of the hospital imaging and histopathology databases in December 2009 for all patients and reports from the medical notes for those referred for rigid cystoscopy. Follow-up was for 21-66 months. RESULTS: The prevalence of bladder cancer in the clinical cohort was 20% (156/778). For the diagnostic strategy using CT urography as an additional test for diagnosing bladder cancer, when scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 1.0 (95% confidence interval [CI] 0.98-1.00), specificity was 0.94 (95% CI 0.91-0.95), the positive predictive value (PPV) was 0.80 (95% CI 0.73-0.85) and the negative predictive value (NPV) was 1.0 (95% CI 0.99-1.00). For the diagnostic strategy using CT urography as a replacement test for flexible cystoscopy for diagnosing bladder cancer, when scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 0.95 (95% CI 0.90-0.97), specificity was 0.83 (95% CI 0.80-0.86), the PPV was 0.58 (95% CI 0.52-0.64), and the NPV was 0.98 (95% CI 0.97-0.99). Similarly using flexible cystoscopy for diagnosing bladder cancer, if scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 0.98 (95% CI 0.94- 0.99), specificity was 0.94 (95% CI 0.92-0.96), the PPV was 0.80 (95% CI 0.73-0.85) and the NPV was 0.99 (95% CI 0.99-1.0). For the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow-up (option 1), patients with a positive CT urography score are referred directly for rigid cystoscopy, and patients with an equivocal or normal score were referred for flexible cystoscopy. Sensitivity was 1.0 (95% CI 0.98-1.0), specificity was 0.94 (95% CI 0.91-0.95), the PPV was 0.80 (95% CI 0.73-0.85), and the NPV was 1.0 (95% CI 0.99-1.0). For the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow-up (option 2), patients with a positive CT urography score are referred directly for rigid cystoscopy, patients with an equivocal score are referred for flexible cystoscopy and patients with a normal score undergo clinical follow-up. Sensitivity was 0.95 (95% CI 0.90-0.97), specificity was 0.98 (95% CI 0.97-0.99), the PPV was 0.93 (95% CI 0.87-0.96), and the NPV was 0.99 (95% CI 0.97-0.99). For voided urine cytology, if scores of 0-3 were classified as negative and 4-5 as positive for bladder cancer, sensitivity was 0.38 (95% CI 0.31-0.45), specificity was 0.98 (95% CI 0.97-0.99), the PPV was 0.82 (95% CI 0.72-0.88) and the NPV was 0.84 (95% CI 0.81-0.87). CONCLUSIONS: There is a clear advantage for the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow-up (option 1), in which patients with a positive CT urography score for bladder cancer are directly referred for rigid cystoscopy, but all other patients undergo flexible cystoscopy. Diagnostic accuracy is the same as for the additional test strategy with the advantage of a 17% reduction of the number of flexible cystoscopies performed. The sensitivity of voided urine cytology is too low to justify its continuing use in a hospital haematuria rapid diagnosis clinic using CT urography and flexible cystoscopy.

Sublingual MV140 for Prevention of Recurrent Urinary Tract Infections.

BACKGROUND: Recurrent urinary tract infections (UTIs), which consist of three or more episodes in 1 year or two or more infections in 6 months, affect 5% to 10% of women. MV140, a sublingual preparation of whole-cell inactivated bacteria, has shown clinical benefit in observational studies. This trial examined treatment with MV140 to prevent recurrent UTI. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group 1-year trial, 240 women 18 to 75 years of age from Spain and the United Kingdom with recurrent UTI were allocated to receive MV140 for 3 or 6 months or placebo for 6 months in a 1:1:1 ratio. The primary end point was the number of UTIs in the 9-month study period after 3 months of intervention. Key secondary end points were the percentage of women who were UTI free over the above period, time to UTI onset, and health-related quality of life. RESULTS: The median (interquartile range) of UTI episodes was 3.0 (0.5 to 6.0) for placebo compared with 0.0 (0.0 to 1.0) in both groups receiving MV140 (P<0.001). Among women treated with placebo, 25% (95% confidence interval [CI], 15% to 35%) were free of UTIs compared with 56% (95% CI, 44% to 67%) and 58% (95% CI, 44% to 67%) of women who received 3 and 6 months of MV140 treatment, respectively. A total of 205 AEs in 101 participants were registered (81, 76, and 48 in the placebo, 3-month MV140, and 6-month MV140 groups, respectively). CONCLUSIONS: In this controlled trial of modest size and duration, MV140 showed promising clinical efficacy in reducing recurrent UTI in women suffering from this condition. Adverse effects were not clinically limiting. (Funded by Inmunotek S.L. and Syner-Med [Pharmaceutical Products] Ltd.; ClinicalTrials.gov number, NCT02543827.)

Essential Research Priorities in Renal Cancer: A Modified Delphi Consensus Statement.

BACKGROUND: Identification of clear and focused research priorities is crucial to drive research forward. OBJECTIVE: To identify research priorities in renal cell carcinoma (RCC) through a multidisciplinary collaboration between clinicians, researchers, and patients. DESIGN, SETTING, AND PARTICIPANTS: In phase I, 44 RCC experts provided 24 literature reviews within their field, summarising research gaps (RGs). Three expert discussion meetings and patient interviews were performed, and 39 potential RGs were identified. In phase II, experts (N=82) scored these gaps on a nine-point scale (1-3: not important; 4-6: important; 7-9: critical) through a multistep Delphi process involving three online surveys and two further consensus meetings. The surveys aimed to reach a consensus, defined as ≥70% agreement by experts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three iterations of the Delphi survey were performed. The results obtained after the third Delphi survey were distributed amongst the RCC experts and patient representatives for final feedback. RESULTS AND LIMITATIONS: In the first Delphi survey, the response rate was 56% (46/82), increasing to 67% (55/82) and 71% (58/82) in the second and third iterations, respectively. Survey respondents included 45.7% urologists, 37.0% oncologists, 8.7% radiologists, and 8.6% other specialists (pathologists, health economists, geneticist, and scientists). The process resulted in the identification of 14 crucial RGs, across a broad range of RCC themes. Key themes included further research into systemic therapies for RCC and management strategies that maximise quality of life, especially in patient groups that are "difficult to treat" and have rarer RCC subtypes. Two crucial RGs relate to biomarkers and novel imaging approaches for both localised and metastatic disease, to enable prognostic risk stratification and individualise patient management. Study participants were from a UK and European setting; therefore, we acknowledge that the RGs identified represent European priorities. CONCLUSIONS: These RGs will facilitate international collaboration towards a concerted attempt to improve patients' survival and quality of life. PATIENT SUMMARY: We formed a collaboration between researchers, clinicians, and patients to identify research priorities in kidney cancer. We identified 14 priorities that will improve patient outcomes by focusing on research efforts.

Targeting vascular endothelial growth factor in renal cell carcinoma.

Renal cancer is the most lethal of all urological malignancies with overall 5-year survival rates of around 60%. The predominant reason for the poor prognosis of this cancer has been the relative lack of effective systemic therapy for advanced metastatic disease. Until recently immunotherapy with interleukin-2 or interferon-alpha has been the standard of care for metastatic renal cell carcinoma (RCC); however, the response rates for these treatments were at best only 3-21%. The use of molecular biological techniques has led to a greater understanding of the genetic basis of RCC. Mutations of the von Hippel-Lindau (VHL) gene on chromosome 3p25 with the resultant overexpression of hypoxia-inducible factors (HIFs) have been shown to lead to the development of clear-cell RCC. The unearthing of the pathways downstream of VHL has led to the development of numerous novel therapies that specifically target HIF-related genes such as vascular endothelial growth factor (VEGF). In this article, we explore the VHL-HIF-VEGF pathway that plays a fundamental role in the development of renal cancer. In addition, we review the evidence base for the use of these new targeted therapies for advanced RCC and uniquely include the latest practice guidelines from the European Association of Urology, the United States National Comprehensive Cancer Network and the National Institute for Health and Clinical Excellence.

A three-centre experience of orthotopic neobladder reconstruction after radical cystectomy: revisiting the initial experience, and results in 104 patients.

OBJECTIVE: To assess, in a retrospective three-centre series, a second analysis of the initial experience and results of patients undergoing radical cystectomy (RC) and orthotopic neobladder reconstruction (ONR) after an additional 4 years of follow-up. PATIENTS AND METHODS: The medical records of 104 suitable consecutive patients undergoing RC and ONR between June 1994 and April 2003 were reviewed retrospectively. The complications, mortality, continence and cancer control rates were all recorded. RESULTS: The median (range) follow-up was 88 (52-156) months; 90 patients had reconstruction with a 'Studer' neobladder, 12 with a Hautmann W pouch and 2 with a 'T pouch' ileal neobladder. There were 24 early complications, and one death after surgery. There were 32 late complications. The daytime continence rate was 98% and the nocturnal continence rate was 76%. Ten patients required intermittent self-catheterization (ISC). In all, 30 patients had local and/or distant recurrences, all of whom died. Seven patients died from other causes. CONCLUSIONS: ONR provides excellent long-term continence rates and both acceptable complication and mortality rates. Suitable patients undergoing RC should be offered ONR.

Setting Research Priorities in Partnership with Patients to Provide Patient-centred Urological Cancer Care.

There is a well-documented discrepancy in prioritisation of research agendas between patients and researchers. Patient involvement in urological research from the outset is critical for well-prioritised research.

Is Erectile Dysfunction an Example of Abnormal Endothelial Function?

Erectile dysfunction (ED) affects approximately half of men during middle age. Erectile dysfunction is often an early symptom of systemic vascular disease, which may precipitate significant cardiac events. The pathophysiology of ED and cardiovascular disease is closely linked. Endothelial dysfunction occurs at an early stage in ED and cardiovascular disease (CVD). In normal conditions, nitric oxide dependent and independent mechanisms regulate penile vascular tone ensuring an appropriate balance of vasoconstriction and vasodilatation. A normal endothelium is responsible for mediating the effect of pro-erectile mediators derived from the endothelium and is critical in normal erectile function. Endothelial dysfunction disrupts the homeostatic mechanisms responsible for regulation of smooth muscle contraction and penile vascular tone. Reduced bioavailability of nitric oxide (NO) occurs as a response to endothelial damage. Phosphodiesterases further degrade levels of cyclic guanosine monophosphate (cGMP) and impair smooth muscle relaxation and erectile function. A number of endothelium derived NO independent mediators of erectile function have been described and are known to contribute to ED in the presence of endothelial damage. This review provides an up to date analysis of the role of the endothelium in ED describing the pathways involved and how these represent current and potential therapeutic targets.

An in vivo hypoxia metagene identifies the novel hypoxia inducible factor target gene SLCO1B3.

A hypoxia-associated gene signature (metagene) was previously derived via in vivo data-mining. In this study, we aimed to investigate whether this approach could identify novel hypoxia regulated genes. From an initial list of nine genes, three were selected for further study (BCAR1, IGF2BP2 and SLCO1B3). Ten cell lines were exposed to hypoxia and interrogated for the expression of the three genes. All three genes were hypoxia inducible in at least one of the 10 cell lines with SLCO1B3 induced in seven. SLCO1B3 was studied further using chromatin immunoprecipitation and luciferase assays to investigate hypoxia inducible factor (HIF) dependent transcription. Two functional HIF response elements were identified within intron 1 of the gene. The functional importance of SLCO1B3 was studied by gene knockdown experiments followed by cell growth assays, flow cytometry and Western blotting. SLCO1B3 knockdown reduced cell size and 3-dimensional spheroid volume, which was associated with decreased activation of the mammalian target of rapamycin (mTOR) pathway. Finally, Oncomine analysis revealed that head and neck and colorectal tumours had higher levels of SLCO1B3 compared to normal tissue. Thus, the knowledge based approach for deriving gene signatures can identify novel biologically relevant genes.

Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy.

BACKGROUND AND PURPOSE: For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation. MATERIALS AND METHODS: Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels. RESULTS: STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions. CONCLUSIONS: This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.

The impact of the two-week wait rule on the diagnosis and management of bladder cancer in a single UK institution.

INTRODUCTION: The objective of this study was to investigate the impact of the 2-week wait rule on patient waiting times for the diagnosis and treatment of bladder cancer. PATIENTS AND METHODS: Data reporting the waiting times from diagnosis to treatment for 100 consecutive patients newly diagnosed with bladder cancer immediately before and after the implementation of the 2-week wait rule were compared. The data were collected both prospectively and retrospectively from cancer multidisciplinary team meeting files and patient records. Various steps of the patient pathway were analysed including waiting times from referral to consultation as well as time to investigation and first treatment. Data were also analysed based upon tumour stage/grade and whether referrals were made on an urgent or routine basis. RESULTS: One hundred newly diagnosed patients with bladder cancer in each group covered a period of 4-5 years (1997-2001 and 2001-2006). Following the introduction of the 2-week wait rule, there was a 47.6% reduction in the time from referral to first consultation with a specialist (42 days vs 22 days; P < 0.001). The time between first investigation and treatment has not reduced significantly. We also found that, despite the introduction of the 2-week wait rule, only 42% of the patients were diagnosed with bladder cancer using this pathway. Patients referred as 'routine' waited longer to be seen in hospital although there was no significant delay in receiving treatment. CONCLUSIONS: The introduction of the 2-week wait rule has significantly reduced the time patients with bladder cancer wait for their first consultation with a specialist. However, there is no significant change in the time between first consultation and treatment.

Laparoscopic cytoreductive nephrectomy: a three-center retrospective analysis.

INTRODUCTION: Metastatic renal cell carcinoma is associated with a poor prognosis. Given the current lack of effective systemic therapies and data suggesting a survival benefit from cytoreductive nephrectomy (CRN) before systemic therapy, we have retrospectively analyzed the experience of laparoscopic cytoreductive nephrectomy (LCRN) in three U.K. centers. The focus of this study was to assess the peri- and postoperative safety and hence feasibility of LCRN in the United Kingdom. PATIENTS AND METHODS: Twenty-five patients with metastatic renal cell carcinoma deemed suitable for systemic therapy underwent LCRN in three U.K. centers over a 4-year period. RESULTS: The tumors ranged from 3.4 cm in diameter to 12 cm. Operating times ranged from 89 (minimum) to 310 minutes (maximum), median 175 minutes. The median amount of blood loss was 150 mL, and hence the transfusion rate was low with only one patient requiring on-table transfusion and two patients requiring additional blood before discharge. Hospital stay ranged between 2.5 and 11 days; median postoperative stay was 3 days. CONCLUSIONS: In our initial experience, LCRN seems safe and feasible with low morbidity and a good perioperative outcome.

MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU.

BACKGROUND: Hypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR-210 (miR-210) which is associated with a poor prognosis. METHODS AND FINDINGS: In human cancer cell lines and tumours, we found that miR-210 targets the mitochondrial iron sulfur scaffold protein ISCU, required for assembly of iron-sulfur clusters, cofactors for key enzymes involved in the Krebs cycle, electron transport, and iron metabolism. Down regulation of ISCU was the major cause of induction of reactive oxygen species (ROS) in hypoxia. ISCU suppression reduced mitochondrial complex 1 activity and aconitase activity, caused a shift to glycolysis in normoxia and enhanced cell survival. Cancers with low ISCU had a worse prognosis. CONCLUSIONS: Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation.