Developing Healthcare Team Observations for Patient Safety (HTOPS): senior medical students capture everyday clinical moments.

BACKGROUND: Aviation has used a real-time observation method to advance anonymised feedback to the front-line and improve safe practice. Using an experiential learning method, this pilot study aimed to develop an observation-based real-time learning tool for final-year medical students with potential wider use in clinical practice. METHODS: Using participatory action research, we collected data on medical students' observations of real-time clinical practice. The observation data was analysed thematically and shared with a steering group of experts to agree a framework for recording observations. A sample of students (observers) and front-line clinical staff (observed) completed one-to-one interviews on their experiences. The interviews were analysed using thematic analysis. RESULTS: Thirty-seven medical students identified 917 issues in wards, theatres and clinics in an acute hospital trust. These issues were grouped into the themes of human influences, work environment and systems. Aviation approaches were adapted to develop an app capable of recording real-time positive and negative clinical incidents. Five students and eleven clinical staff were interviewed and shared their views on the value of a process that helped them learn and has the potential to advance the quality of practice. Concerns were shared about how the observational process is managed. CONCLUSION: The study developed an app (Healthcare Team Observations for Patient Safety-HTOPS), for recording good and poor clinical individual and team behaviour in acute-care practice. The process advanced medical student learning about patient safety. The tool can identify the totality of patient safety practice and illuminate strength and weakness. HTOPS offers the opportunity for collective ownership of safety concerns without blame and has been positively received by all stakeholders. The next steps will further refine the app for use in all clinical areas for capturing light noise.

Major Urological Cancer Surgery for Patients is Safe and Surgical Training Should Be Encouraged During the COVID-19 Pandemic: A Multicentre Analysis of 30-day Outcomes.

COVID-19 has resulted in the deferral of major surgery for genitourinary (GU) cancers with the exception of cancers with a high risk of progression. We report outcomes for major GU cancer operations, namely radical prostatectomy (RP), radical cystectomy (RC), radical nephrectomy (RN), partial nephrectomy (PN), and nephroureterectomy performed at 13 major GU cancer centres across the UK between March 1 and May 5, 2020. A total of 598 such operations were performed. Four patients (0.7%) developed COVID-19 postoperatively. There was no COVID-19-related mortality at 30 d. A minimally invasive approach was used in 499 cases (83.4%). A total of 228 cases (38.1%) were described as training procedures. Training case status was not associated with a higher American Society of Anesthesiologists (ASA) score (p = 0.194) or hospital length of stay (LOS; p > 0.05 for all operation types). The risk of contracting COVID-19 was not associated with longer hospital LOS (p = 0.146), training case status (p = 0.588), higher ASA score (p = 0.295), or type of hospital site (p = 0.303). Our results suggest that major surgery for urological cancers remains safe and training should be encouraged during the ongoing COVID-19 pandemic provided appropriate countermeasures are taken. These real-life data are important for policy-makers and clinicians when counselling patients during the current pandemic. PATIENT SUMMARY: We collected outcome data for major operations for prostate, bladder, and kidney cancers during the COVID-19 pandemic. These surgeries remain safe and training should be encouraged during the ongoing pandemic provided appropriate countermeasures are taken. Our real-life results are important for policy-makers and clinicians when counselling patients during the COVID-19 pandemic.

Surgeon-Team Separation in Robotic Theaters: A Qualitative Observational and Interview Study.

BACKGROUND: The rapid uptake of robotic surgery has largely been driven by the improved technical aspects of minimally invasive surgery including improved ergonomics, wristed instruments, and 3-dimensional vision. However, little attention has been given to the effect of physical separation of the surgeon from the rest of the operating team. PURPOSE: The aim of this study was to examine in depth how this separation affected team dynamics and staff emotions. METHODS: Robotic procedures were observed in 2 tertiary hospitals, and laparoscopic/open procedures were added for comparison; field notes were taken instantaneously. One-to-one interviews with theater team members were audio recorded and transcribed verbatim. Qualitative analysis was conducted via grounded theory approach using NVIVO11. RESULTS: Twenty-nine participants (26 interviewed) were recruited to the study (11 females) and 134 (109 robotic) hours of observation were completed across gynecology, urology, and colorectal surgery.The following 3 main themes emerged with compounding factors identified: (a) communication challenge, (b) immersion versus distraction, and (c) emotional impact. Compounding factors included the following: individual and team experience, staffing levels, and the physical theater environment. CONCLUSIONS: Our emergent theory is that "surgeon-team separation in robotic theaters poses communication challenges which impacts on situational awareness and staff emotions." These can be ameliorated by staff training, increased experience, and team/procedure consistency.

Radiofrequency-induced Thermo-chemotherapy Effect Versus a Second Course of Bacillus Calmette-Guérin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guérin Therapy (HYMN): A Phase III, Open-label, Randomised Controlled Trial.

BACKGROUND: There is no effective intravesical second-line therapy for non-muscle-invasive bladder cancer (NMIBC) when bacillus Calmette-Guérin (BCG) fails. OBJECTIVE: To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/maintenance BCG. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 (HYMN [ClinicalTrials.gov: NCT01094964]). INTERVENTION: Patients were randomly assigned (1:1) to RITE (60min, 40mg mitomycin-C, 42±2°C) or control following stratification for carcinoma in situ (CIS) status (present/absent), therapy history (failure of previous induction/maintenance BCG), and treatment centre. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measures were DFS and complete response (CR) at 3 mo for the CIS at randomisation subgroup. Analysis was based on intention-to-treat. RESULTS AND LIMITATIONS: A total of 104 patients were randomised (48 RITE: 56 control). Median follow-up for the 31 patients without a DFS event was 36 mo. There was no significant difference in DFS between treatment arms (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.84-2.10, p=0.23) or in 3-mo CR rate in CIS patients (n=71; RITE: 30% vs control: 47%, p=0.15). There was no significant difference in DFS between treatment arms in non-CIS patients (n=33; RITE: 53% vs control: 24% at 24 mo, HR 0.50, 95% CI 0.22-1.17, p=0.11). DFS was significantly lower in RITE than in control in CIS with/without papillary patients (n=71; HR 2.06, 95% CI 1.17-3.62, p=0.01; treatment-subgroup interaction p=0.007). Disease progression was observed in four patients in each treatment arm. Adverse events and health-related quality of life between treatment arms were comparable. CONCLUSIONS: DFS was similar between RITE and control. RITE may be a second-line therapy for non-CIS recurrence following BCG failure; however, confirmatory trials are needed. RITE patients with CIS with/without papillary had lower DFS than control. HYMN highlights the importance of the control arm when evaluating novel therapies. PATIENT SUMMARY: This study did not show a difference in bladder cancer outcomes between microwave-heated chemotherapy and standard of care treatment. Papillary bladder lesions may benefit from microwave-heated chemotherapy treatment; however, more research is needed. Both treatments are similarly well tolerated.

Is Immediate Radical Cystectomy Necessary for All Patients with Non-Muscle-Invasive Micropapillary Bladder Cancer?

INTRODUCTION: We aim to review the outcomes of micropapillary urothelial carcinoma (MPUC) of the bladder from a single institution. The hypothesis is that non-muscle-invasive (NMI) MPUC may have a heterogeneous prognosis, and detailed pathological analysis may identify patients that could be managed without immediate cystectomy. PATIENTS AND METHODS: This is a retrospective analysis of patients presenting with MPUC in a primary transurethral resection specimen (n = 40). The pattern of micropapillary (MP) differentiation [surface/non-invasive (sMP) or invasive (iMP)], extent of MP differentiation and lymphovascular invasion (LVI) were correlated with overall survival (OS), recurrence-free survival and upstaging at re-resection. RESULTS: Sixteen of 40 patients died after a median follow-up of 37 months. Tumour stage was strongly predictive of OS (p < 0.0001). LVI was associated with increased mortality (hazard ratio 12.4, 95% CI: 3.5-44.5, p = 0.0001), higher pathological stage (p = 0.001), lymph node involvement (p = 0.001) and iMP differentiation (p = 0.006). In NMI patients not undergoing cystectomy (n = 17), NMI-sMP compared with NMI-iMP differentiation was associated with an improved OS when compared with iMP (63 vs. 47 months, p = 0.05). CONCLUSIONS: MPUC is an aggressive variant of urothelial carcinoma (UC). Similar to conventional UC, LVI associated with MPUC is an adverse prognostic indicator. iMP is a morphological marker for LVI. Histopathological reports should distinguish between sMP and iMP differentiation.

Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo.

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In this study we first show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids and intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Second, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression.

Systematic review of adrenalectomy and lymph node dissection in locally advanced renal cell carcinoma.

CONTEXT: Controversy remains over whether adrenalectomy and lymph node dissection (LND) should be performed concomitantly with radical nephrectomy (RN) for locally advanced renal cell carcinoma (RCC) cT3-T4N0M0. OBJECTIVE: To systematically review all relevant literature comparing oncologic, perioperative, and quality-of-life (QoL) outcomes for locally advanced RCC managed with RN with or without concomitant adrenalectomy or LND. EVIDENCE ACQUISITION: Relevant databases were searched up to August 2012. Randomised controlled trials (RCTs) and comparative studies were included. Outcome measures were overall survival, QoL, and perioperative adverse effects. Risks of bias (RoB) were assessed using Cochrane RoB tools. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. EVIDENCE SYNTHESIS: A total of 3658 abstracts and 252 full-text articles were screened. Eight studies met the inclusion criteria: six LNDs (one RCT and five nonrandomised studies [NRSs]) and two adrenalectomies (two NRSs). RoB was high across the evidence base, and the quality of evidence from outcomes ranged from moderate to very low. Meta-analyses were not undertaken because of diverse study designs and data heterogeneity. There was no significant difference in survival between the groups, even though 5-yr overall survival appears better for the RN plus LND group compared with the no-LND group in one randomised study. There was no evidence of a difference in adverse events between the RN plus LND and no-LND groups. No studies reported QoL outcomes. There was no evidence of an oncologic difference between the RN with adrenalectomy and RN without adrenalectomy groups. No studies reported adverse events or QoL outcomes. CONCLUSIONS: There is insufficient evidence to draw any conclusions on oncologic outcomes for patients having concomitant LND or ipsilateral adrenalectomy compared with patients having RN alone for cT3-T4N0M0 RCC. The quality of evidence is generally low and the results potentially biased. Further research in adequately powered trials is needed to answer these questions.

Current perspectives in bladder cancer management.

More than 350,000 new cases of bladder cancer are diagnosed worldwide each year; the vast majority (> 90%) of these are transitional cell carcinomas (TCC). The most important risk factors for the development of bladder cancer are smoking and occupational exposure to toxic chemicals. Painless visible haematuria is the most common presenting symptom of bladder cancer; significant haematuria requires referral to a specialist urology service. Cystoscopy and urine cytology are currently the recommended tools for diagnosis of bladder cancer. Excluding muscle invasion is an important diagnostic step, as outcomes for patients with muscle invasive TCC are less favourable. For non-muscle invasive bladder cancer, transurethral resection followed by intravesical chemotherapy (typically Mitomycin C or epirubicin) or immunotherapy [bacillus Calmette-Guérin (BCG)] is the current standard of care. For patients failing BCG therapy, cystectomy is recommended; for patients unsuitable for surgery, the choice of treatment options is currently limited. However, novel interventions, such as chemohyperthermia and electromotive drug administration, enhance the effects of conventional chemotherapeutic agents and are being evaluated in Phase III trials. Radical cystectomy (with pelvic lymphadenectomy and urinary diversion) or radical radiotherapy are the current established treatments for muscle invasive TCC. Neoadjuvant chemotherapy is recommended before definitive treatment of muscle invasive TCC; cisplatin-containing combination chemotherapy is the recommended regimen. Palliative chemotherapy is the first-choice treatment in metastatic TCC.

Systematic review of perioperative and quality-of-life outcomes following surgical management of localised renal cancer.

CONTEXT: For the treatment of localised renal cell carcinoma (RCC), uncertainties remain over the perioperative and quality-of-life (QoL) outcomes for the many different surgical techniques and approaches of nephrectomy. Controversy also remains on whether newer minimally invasive nephron-sparing interventions offer better QoL and perioperative outcomes, and whether adrenalectomy and lymphadenectomy should be performed simultaneously with nephrectomy. These non-oncological outcomes are important because they may have a considerable impact on localised RCC treatment decision making. OBJECTIVE: To review systematically all the relevant published literature comparing perioperative and QoL outcomes of surgical management of localised RCC (T1-2N0M0). EVIDENCE ACQUISITION: Relevant databases including Medline, Embase, and the Cochrane Library were searched up to January 2012. Randomised controlled trials (RCTs) or quasi-randomised controlled trials, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The outcome measures were QoL, analgesic requirement, length of hospital stay, time to normal activity level, surgical morbidity and complications, ischaemia time, renal function, blood loss, length of operation, need for blood transfusion, and perioperative mortality. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation. EVIDENCE SYNTHESIS: A total of 4580 abstracts and 380 full-text articles were assessed, and 29 studies met the inclusion criteria (7 RCTs and 22 NRSs). There were high risks of bias and low-quality evidence for studies meeting the inclusion criteria. There is good evidence indicating that partial nephrectomy results in better preservation of renal function and better QoL outcomes than radical nephrectomy regardless of technique or approach. Regarding radical nephrectomy, the laparoscopic approach has better perioperative outcomes than the open approach, and there is no evidence of a difference between the transperitoneal and retroperitoneal approaches. Alternatives to standard laparoscopic radical nephrectomy (LRN) such as hand-assisted, robot-assisted, or single-port techniques appear to have similar perioperative outcomes. There is no good evidence to suggest that minimally invasive procedures such as cryotherapy or radiofrequency ablation have superior perioperative or QoL outcomes to nephrectomy. Regarding concomitant lymphadenectomy during nephrectomy, there were low event rates for complications, and no definitive difference was observed. There was no evidence to base statements about concomitant ipsilateral adrenalectomy during nephrectomy. CONCLUSIONS: Partial nephrectomy results in significantly better preservation of renal function over radical nephrectomy. For tumours where partial nephrectomy is not technically feasible, there is no evidence that alternative procedures or techniques are better than LRN in terms of perioperative or QoL outcomes. In making treatment decisions, perioperative and QoL outcomes should be considered in conjunction with oncological outcomes. Overall, there was a paucity of data regarding QoL outcomes, and when reported, both QoL and perioperative outcomes were inconsistently defined, measured, or reported. The current evidence base has major limitations due to studies of low methodological quality marked by high risks of bias.

Systematic review of oncological outcomes following surgical management of localised renal cancer.

CONTEXT: Renal cell carcinoma (RCC) accounts for 2-3% of adult malignancies. There remain uncertainties over the oncological outcomes for the surgical management of localised RCC. OBJECTIVE: Systematically review relevant literature comparing oncological outcomes of surgical management of localised RCC (T1-2N0M0). EVIDENCE ACQUISITION: Relevant databases including Medline, Embase, and the Cochrane Library were searched up to October 2010, and an updated scoping search was performed up to January 2012. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The main outcomes were overall survival, cancer-specific survival, recurrence, and metastases. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). EVIDENCE SYNTHESIS: A total of 4580 abstracts and 389 full-text articles were assessed. Thirty-four studies met the inclusion criteria (6 RCTs and 28 NRSs). Meta-analyses were planned but were deemed inappropriate due to data heterogeneity. There were high risks of bias and low-quality evidence across the evidence base. Open radical nephrectomy and open partial nephrectomy showed similar cancer-specific and overall survival, but when both open and laparoscopic approaches are considered together, the evidence showed improved survival for partial nephrectomy for tumours ≤4cm. The overall evidence suggests either equivalent or better survival with partial nephrectomy. Laparoscopic radical nephrectomy offered equivalent survival to open radical nephrectomy, and all laparoscopic approaches achieved equivalent survival. Open and laparoscopic partial nephrectomy achieved equivalent survival. The issue of ipsilateral adrenalectomy or complete lymph node dissection with radical nephrectomy or partial nephrectomy remains unresolved. CONCLUSIONS: The evidence base suggests localised RCCs are best managed by nephron-sparing surgery where technically feasible. However, the current evidence base has significant limitations due to studies of low methodological quality marked by high risks of bias.

Urological cancer care pathways: development and use in the context of systematic reviews and clinical practice guidelines.

BACKGROUND: Making healthcare treatment decisions is a complex process involving a broad stakeholder base including patients, their families, health professionals, clinical practice guideline developers and funders of healthcare. METHODS: This paper presents a review of a methodology for the development of urological cancer care pathways (UCAN care pathways), which reflects an appreciation of this broad stakeholder base. The methods section includes an overview of the steps in the development of the UCAN care pathways and engagement with clinical content experts and patient groups. RESULTS: The development process is outlined, the uses of the urological cancer care pathways discussed and the implications for clinical practice highlighted. The full set of UCAN care pathways is published in this paper. These include care pathways on localised prostate cancer, locally advanced prostate cancer, metastatic prostate cancer, hormone-resistant prostate cancer, localised renal cell cancer, advanced renal cell cancer, testicular cancer, penile cancer, muscle invasive and metastatic bladder cancer and non-muscle invasive bladder cancer. CONCLUSION: The process provides a useful framework for improving urological cancer care through evidence synthesis, research prioritisation, stakeholder involvement and international collaboration. Although the focus of this work is urological cancers, the methodology can be applied to all aspects of urology and is transferable to other clinical specialties.

Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: Systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to assess the test performance and clinical effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC) in people suspected of new or recurrent bladder cancer. METHODS: A systematic review was conducted of randomized controlled trials (RCTs), nonrandomized comparative studies, or diagnostic cross-sectional studies comparing PDD with WLC. Fifteen electronic databases and Web sites were searched (last searches April 2008). For clinical effectiveness, only RCTs were considered. RESULTS: Twenty-seven studies (2,949 participants) assessed test performance. PDD had higher sensitivity than WLC (92 percent, 95 percent confidence interval [CI], 80-100 percent versus 71 percent, 95 percent CI, 49-93 percent) but lower specificity (57 percent, 95 percent CI, 36-79 percent versus 72 percent, 95 percent CI, 47-96 percent). For detecting higher risk tumors, median range sensitivity of PDD (89 percent [6-100 percent]) was higher than WLC (56 percent [0-100 percent]) whereas for lower risk tumors it was broadly similar (92 percent [20-95 percent] versus 95 percent [8-100 percent]). Four RCTs (709 participants) using 5-aminolaevulinic acid (5-ALA) as the photosensitising agent reported clinical effectiveness. Using PDD at transurethral resection of bladder tumor (TURBT) resulted in fewer residual tumors at check cystoscopy (relative risk [RR], 0.37, 95 percent CI, 0.20-0.69) and longer recurrence-free survival (RR, 1.37, 95 percent CI, 1.18-1.59), compared with WLC. CONCLUSIONS: PDD detects more bladder tumors than WLC, including more high-risk tumors. Based on four RCTs reporting clinical effectiveness, 5-aminolaevulinic acid-mediated PDD at TURBT facilitates a more complete resection and prolongs recurrence-free survival.

Management of the distal ureter during nephroureterectomy for upper urinary tract transitional cell carcinoma: a review.

INTRODUCTION: The standard treatment for upper urinary tract transitional cell carcinoma (UUT-TCC) is open radical nephroureterectomy with excision of a bladder cuff. We assess the successful endoscopic completion and oncological efficacy of the various minimally invasive transurethral techniques devised for the management of the intramural ureter during nephroureterectomy. MATERIALS AND METHODS: A comprehensive review of the English literature until February 2009 using the PubMed database returned 42 relevant papers. Five methods of endoscopic management of the distal ureter were identified and compared to the open technique. RESULTS: There are no randomised studies. Successful completion of the endoscopic procedure was less (91%) for the ureteric stripping technique than for the other endoscopic modalities (99.8-100%). Recurrences were highest for laparoscopic extravesical ureteric stapling in conjunction with cystoscopic detachment of the ureter, although the numbers analysed were small. For the other endoscopic modalities, bladder recurrence, positive margins and retroperitoneal recurrence (20-37, 0-4 and 1-3%, respectively) in case series were similar compared with the open method (36, 5 and 3%, respectively). CONCLUSIONS: Current non-randomised evidence is open to selection bias and is insufficient to support or refute endoscopic management of the distal ureter as an alternative to open bladder cuff excision. We highlight the reported inefficiency of the ureteric stripping technique.

Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.

OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC), and urine biomarkers [fluorescence in situ hybridisation (FISH), ImmunoCyt, NMP22] and cytology for the detection and follow-up of bladder cancer. DATA SOURCES: Major electronic databases including MEDLINE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register were searched until April 2008. REVIEW METHODS: A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic and follow-up strategies for the diagnosis and management of patients with bladder cancer. RESULTS: In total, 27 studies reported PDD test performance. In pooled estimates [95% confidence interval (CI)] for patient-level analysis, PDD had higher sensitivity than WLC [92% (80% to 100%) versus 71% (49% to 93%)] but lower specificity [57% (36% to 79%) versus 72% (47% to 96%)]. Similar results were found for biopsy-level analysis. The median sensitivities (range) of PDD and WLC for detecting lower risk, less aggressive tumours were similar for patient-level detection [92% (20% to 95%) versus 95% (8% to 100%)], but sensitivity was higher for PDD than for WLC for biopsy-level detection [96% (88% to 100%) versus 88% (74% to 100%)]. For more aggressive, higher-risk tumours the median sensitivity of PDD for both patient-level [89% (6% to 100%)] and biopsy-level [99% (54% to 100%)] detection was higher than those of WLC [56% (0% to 100%) and 67% (0% to 100%) respectively]. Four RCTs comparing PDD with WLC reported effectiveness outcomes. PDD use at transurethral resection of bladder tumour resulted in fewer residual tumours at check cystoscopy [relative risk, RR, 0.37 (95% CI 0.20 to 0.69)] and longer recurrence-free survival [RR 1.37 (95% CI 1.18 to 1.59)] compared with WLC. In 71 studies reporting the performance of biomarkers and cytology in detecting bladder cancer, sensitivity (95% CI) was highest for ImmunoCyt [84% (77% to 91%)] and lowest for cytology [44% (38% to 51%)], whereas specificity was highest for cytology [96% (94% to 98%)] and lowest for ImmunoCyt [75% (68% to 83%)]. In the cost-effectiveness analysis the most effective strategy in terms of true positive cases (44) and life-years (11.66) [flexible cystoscopy (CSC) and ImmunoCyt followed by PDD in initial diagnosis and CSC followed by WLC in follow-up] had an incremental cost per life-year of over 270,000 pounds. The least effective strategy [cytology followed by WLC in initial diagnosis (average cost over 20 years 1403 pounds, average life expectancy 11.59)] was most likely to be considered cost-effective when society's willingness to pay was less than 20,000 pounds per life-year. No strategy was cost-effective more than 50% of the time, but four of the eight strategies in the probabilistic sensitivity analysis (three involving a biomarker or PDD) were each associated with a 20% chance of being considered cost-effective. In sensitivity analyses the results were most sensitive to the pretest probability of disease (5% in the base case). CONCLUSIONS: The advantages of PDD's higher sensitivity in detecting bladder cancer have to be weighed against the disadvantages of a higher false-positive rate. Taking into account the assumptions made in the model, strategies involving biomarkers and/or PDD provide additional benefits at a cost that society might be willing to pay. Strategies replacing WLC with PDD provide more life-years but it is unclear whether they are worth the extra cost.

Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells.

Survival rate of patients diagnosed with the invasive form of bladder cancer is low suggesting an urgent need to implement novel treatments. GTC (gemcitabine, paclitaxel and cisplatin) is a new chemotherapeutic regimen, which has shown promise in clinical trials. Given that receptor tyrosine kinases of the ErbB family are overexpressed in a high proportion of metastatic bladder tumours, approaches involving small-molecule inhibitors of ErbB receptors in combination with conventional cytostatic drugs are of potential interest. Here, we show that the dual inhibitor of ErbB receptors, lapatinib, enhances cytostatic and induces cytotoxic effects of GTC in two bladder cancer cell lines which differ with regard to expression levels of proteins taking part in the ErbB pathway. Lapatinib inhibited phosphorylation of ErbB receptors and also reduced the level of phosphorylated AKT. Flow cytometry analysis demonstrated that GTC treatment affects cell cycle distribution differently in the presence or absence of lapatinib. In RT112 cells, which express high levels of ErbB receptors and harbour wild-type p53, combined GTC/lapatinib treatment resulted in the phosphorylation of p53 at Ser46 and accumulation of sub-G1 cell populations. Our data indicate that a combinatorial approach involving GTC and lapatinib may have therapeutic potential in a subset of bladder tumours depending on the genetic context.