Study protocol for neuromuscular stimulation for rehabilitation after general and vascular surgery: a pilot randomised clinical study.

OBJECTIVES: To investigate the acceptability and safety of neuromuscular stimulation (NMES) as an adjunct for rehabilitation after vascular and general surgery. METHODS AND ANALYSIS: Prospective, single-centre, single-blind, parallel group, randomised controlled study. This study will be conducted in a single-centre, secondary care setting (National Healthcare Service Hospital) in the UK. All patients aged over 18 years undergoing vascular or general surgery with Rockwood Frailty Score of 3 or above on admission. Exclusion is inability or unwillingness to participate in trial, implanted electrical device, pregnancy and acute deep vein thrombosis. Target number of recruitment is 100. Participants will be randomly assigned to active NMES group (group A) or placebo NMES group (group B) prior to surgery. Participants will be blinded and asked to use the NMES device, 1-6 sessions daily (30 min per session) after surgery in addition to standard National Health Service rehabilitation care until discharge. The primary study outcomes are acceptability and safety of NMES assessed by the device satisfaction questionnaire on discharge and adverse events recorded during hospital stay. The secondary outcomes are the postoperative recovery and cost-effectiveness compared between two groups, assessed by various activity tests, mobility and independence measures and questionnaires. ETHICS AND DISSEMINATION: Ethical approvals were provided by London-Harrow Research Ethics Committee (REC) and the Health Research Authority (HRA), Ref: 21/PR/0250. Findings will be published in a peer-reviewed journal and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04784962.

Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

A Comparison of Prostate Cancer Detection between Visual Estimation (Cognitive Registration) and Image Fusion (Software Registration) Targeted Transperineal Prostate Biopsy.

PURPOSE: We compared clinically significant prostate cancer detection by visual estimation and image fusion targeted transperineal prostate biopsy. MATERIALS AND METHODS: This multicenter study included patients with multiparametric magnetic resonance imaging lesions undergoing visual estimation or image fusion targeted transperineal biopsy (April 2017-March 2020). Propensity score matching was performed using demographics (age and ethnicity), clinical features (prostate specific antigen, prostate volume, prostate specific antigen density and digital rectal examination), multiparametric magnetic resonance imaging variables (number of lesions, PI-RADS® score, index lesion diameter, whether the lesion was diffuse and radiological T stage) and biopsy factors (number of cores, operator experience and anesthetic type). Matched groups were compared overall and by operator grade, PI-RADS score, lesion multiplicity, prostate volume and anesthetic type using targeted-only and targeted plus systematic histology. Multiple clinically significant prostate cancer thresholds were evaluated (primary: Gleason ≥3+4). RESULTS: A total of 1,071 patients with a median age of 67.3 years (IQR 61.3-72.4), median prostate specific antigen of 7.5 ng/ml (IQR 5.3-11.2) and 1,430 total lesions underwent targeted-only biopsies (visual estimation: 372 patients, 494 lesions; image fusion: 699 patients, 936 lesions). A total of 770 patients with a median age of 67.4 years (IQR 61-72.1), median prostate specific antigen of 7.1 ng/ml (IQR 5.2-10.6) and 919 total lesions underwent targeted plus systematic biopsies (visual estimation: 271 patients, 322 lesions; image fusion: 499 patients, 597 lesions). Matched comparisons demonstrated no overall difference in clinically significant prostate cancer detection between visual estimation and image fusion (primary: targeted-only 54% vs 57.4%, p=0.302; targeted plus systematic 51.2% vs 58.2%, p=0.123). Senior urologists had significantly higher detection rates using image fusion (primary: targeted-only 45.4% vs 63.7%, p=0.001; targeted plus systematic 39.4% vs 64.5%, p <0.001). CONCLUSIONS: We found no overall difference in clinically significant prostate cancer detection, although image fusion may be superior in experienced hands.

Delayed blood transfusion is associated with mortality following radical cystectomy.

Objectives: To examine the temporal association between blood transfusion and 90-day mortality in patients with bladder cancer treated with radical cystectomy.Methods: This represents a retrospective cohort study of patients treated with radical cystectomy within the Premier Hospital network between 2003 and 2015. Patients outcomes were stratified those who received early blood transfusion (day of surgery) vs delayed blood transfusion (postoperative day ≥1) during the index admission. Primary end point was 90-day mortality following surgery.Results: The median age of 12,056 patients identified was 70 years. A total of 7,201 (59.7%) patients received blood transfusion. Within 90 days following surgery, 57 (2.2%), 162 (5.9%) and 123 (6.7%) patients in the early, delayed and both early and delayed transfused patients died respectively. Following multivariate logistic regression to account for patient (age and Charlson Comorbidity Index [CCI]) and hospital (surgeon volume, surgical approach and academic status) factors, delayed blood transfusion was independently associated with 90-day mortality (Odds ratio [OR], 2.64; 95% Confidence Interval [CI], 1.98-3.53; p < 0.001). A sensitivity analysis defining early blood transfusion as <2 days postoperatively, increased 90-day mortality persisted in patients receiving delayed transfusion (OR, 2.20; 95% CI, 1.63-3.00; p < 0.001). Older patients (≥77 years) with the highest CCI (≥2) had a 7% absolute increase in the predicted probability of 90-day mortality if they were transfused late compared to patients transfused early.Conclusion: Patient undergoing cystectomy may benefit from expedited transfusion to prevent subsequent clinical deterioration which may lead to patient mortality. Future work is needed to elucidate the optimal timing of blood transfusion.

Understanding virtual urology clinics: a systematic review.

OBJECTIVES: To perform a systematic review to identify the clinical, fiscal and environmental evidence on the use of urological telehealth and/or virtual clinic (VC) strategies, and to highlight research gaps in this rapidly evolving field. METHODS: Our PROSPERO-registered (CRD42019151946) systematic search of Embase, Medline and the Cochrane Review Database was performed to identify original research articles pertaining to adult urology telehealth or VC strategies. Risk-of-bias (RoB) assessment was performed according to the Cochrane 2.0 RoB tool or the Joanna Briggs Institute Checklist for non-randomized studies. RESULTS: A total of 5813 participants were included from 18 original articles (two randomized controlled trials [RCTs], 10 prospective studies, six retrospective studies). Urology sub-specialities comprised: uro-oncology (n = 6); general urology (n = 8); endo-urology (n = 2); and lower urinary tract symptoms and/or incontinence (n = 2). Across all sub-specialties, prospective studies using VCs reported a primary median (interquartile range [IQR]) VC discharge rate of 16.6 (14.7-29.8)% and a primary median (IQR) face-to-face (FTF) clinic referral rate of 32.4 (15.5-53.3)%. Direct cost analysis demonstrated median (IQR) annual cost savings of £56 232 (£46 260-£61 116). Grade II and IIIb complications were reported in two acute ureteric colic studies, with rates of 0.20% (3/1534) and 0.13% (2/1534), respectively. The annual carbon footprint avoided ranged from 0.7 to 4.35 metric tonnes of CO2 emissions, depending on the mode of transport used. Patient satisfaction was inconsistently reported, and assessments lacked prospective evaluation using validated questionnaires. CONCLUSION: Urology VCs are a promising new platform which can offer clinical, financial and environmental benefits to support an increasing urological referral burden. Further prospective evidence is required across urological sub-specialties to confirm equivalency and safety against traditional FTF assessment.

Challenges of early renal cancer detection: symptom patterns and incidental diagnosis rate in a multicentre prospective UK cohort of patients presenting with suspected renal cancer.

OBJECTIVES: To describe the frequency and nature of symptoms in patients presenting with suspected renal cell carcinoma (RCC) and examine their reliability in achieving early diagnosis. DESIGN: Multicentre prospective observational cohort study. SETTING AND PARTICIPANTS: Eleven UK centres recruiting patients presenting with suspected newly diagnosed RCC. Symptoms reported by patients were recorded and reviewed. Comprehensive clinico-pathological and outcome data were also collected. OUTCOMES: Type and frequency of reported symptoms, incidental diagnosis rate, metastasis-free survival and cancer-specific survival. RESULTS: Of 706 patients recruited between 2011 and 2014, 608 patients with a confirmed RCC formed the primary study population. The majority (60%) of patients were diagnosed incidentally. 87% of patients with stage Ia and 36% with stage III or IV disease presented incidentally. Visible haematuria was reported in 23% of patients and was commonly associated with advanced disease (49% had stage III or IV disease). Symptomatic presentation was associated with poorer outcomes, likely reflecting the presence of higher stage disease. Symptom patterns among the 54 patients subsequently found to have a benign renal mass were similar to those with a confirmed RCC. CONCLUSIONS: Raising public awareness of RCC-related symptoms as a strategy to improve early detection rates is limited by the fact that related symptoms are relatively uncommon and often associated with advanced disease. Greater attention must be paid to the feasibility of screening strategies and the identification of circulating diagnostic biomarkers.

A Novel, non-invasive Test Enabling Bladder Cancer Detection in Urine Sediment of Patients Presenting with Haematuria-A Prospective Multicentre Performance Evaluation of ADXBLADDER.

Bladder cancer is the sixth most commonly diagnosed cancer in the European Union. Here, we evaluate the performance of a novel, commercially available enzyme-linked immunosorbent assay utilising MCM5 antibodies (ADXBLADDER; Arquer Diagnostics Ltd, Sunderland, UK) for the detection of bladder cancer, in a blinded, prospective study of 856 patients, across seven centres, presenting with haematuria. The results were compared with the patients' clinical data and final diagnosis as defined by the results of the imaging and cystoscopy, with a prevalence of bladder cancer of 8.6%. ADXBLADDER detected bladder tumours in 54/74 cancers, giving overall sensitivity of 73.0% and an overall negative predictive value (NPV) of 96.4%. Sensitivity and NPV of ADXBLADDER were highest in muscle-invasive bladder cancer, both at 100%, and on analysis of non-pTa (pT1 and above) tumours, the sensitivity for detection was 97% with an NPV of 99.8%. A subset of 173 patients had matching cytology data; of these patients, 18 were positive for bladder cancer. ADXBLADDER detected 16/18 of these cancers, whilst cytology was positive in only four of 18, providing evidence that ADXBLADDER may be a more sensitive test for bladder cancer than standard urine cytology. PATIENT SUMMARY: We conducted a large clinical study of a novel, simple urine test (ADXBLADDER), which measures a protein (MCM5) in urine and can be used to detect bladder cancer in patients. We recruited 856 patients and demonstrated that the new urine test can detect bladder cancer with a high degree of accuracy, performing better than the most commonly used urine test-urine cytology. In conclusion, this novel ADXBLADDER urine test can be used to help detect bladder cancers and it can replace the current, standard urine test.

Likert vs PI-RADS v2: a comparison of two radiological scoring systems for detection of clinically significant prostate cancer.

OBJECTIVE: To compare the clinical validity and utility of Likert assessment and the Prostate Imaging Reporting and Data System (PI-RADS) v2 in the detection of clinically significant and insignificant prostate cancer. PATIENTS AND METHODS: A total of 489 pre-biopsy multiparametric magnetic resonance imaging (mpMRI) scans in consecutive patients were subject to prospective paired reporting using both Likert and PI-RADS v2 by expert uro-radiologists. Patients were offered biopsy for any Likert or PI-RADS score ≥4 or a score of 3 with PSA density ≥0.12 ng/mL/mL. Utility was evaluated in terms of proportion biopsied, and proportion of clinically significant and insignificant cancer detected (both overall and on a 'per score' basis). In those patients biopsied, the overall accuracy of each system was assessed by calculating total and partial area under the receiver-operating characteristic (ROC) curves. The primary threshold of significance was Gleason ≥3 + 4. Secondary thresholds of Gleason ≥4 + 3, Ahmed/UCL1 (Gleason ≥4 + 3 or maximum cancer core length [CCL] ≥6 or total CCL≥6) and Ahmed/UCL2 (Gleason ≥3 + 4 or maximum CCL ≥4 or total CCL ≥6) were also used. RESULTS: The median (interquartile range [IQR]) age was 66 (60-72) years and the median (IQR) prostate-specific antigen level was 7 (5-10) ng/mL. A similar proportion of men met the biopsy threshold and underwent biopsy in both groups (83.8% [Likert] vs 84.8% [PI-RADS v2]; P = 0.704). The Likert system predicted more clinically significant cancers than PI-RADS across all disease thresholds. Rates of insignificant cancers were comparable in each group. ROC analysis of biopsied patients showed that, although both scoring systems performed well as predictors of significant cancer, Likert scoring was superior to PI-RADS v2, exhibiting higher total and partial areas under the ROC curve. CONCLUSIONS: Both scoring systems demonstrated good diagnostic performance, with similar rates of decision to biopsy. Overall, Likert was superior by all definitions of clinically significant prostate cancer. It has the advantages of being flexible, intuitive and allowing inclusion of clinical data. However, its use should only be considered once radiologists have developed sufficient experience in reporting prostate mpMRI.

UK Multicenter Prospective Evaluation of the Leibovich Score in Localized Renal Cell Carcinoma: Performance has Altered Over Time.

OBJECTIVE: To examine changes in outcome by the Leibovich score using contemporary and historic cohorts of patients presenting with renal cell carcinoma (RCC) PATIENTS AND METHODS: Prospective observational multicenter cohort study, recruiting patients with suspected newly diagnosed RCC. A historical cohort of patients was examined for comparison. Metastasis-free survival (MFS) formed the primary outcome measure. Model discrimination and calibration were evaluated using Cox proportional hazard regression and the Kaplan-Meier method. Overall performance of the Leibovich model was assessed by estimating explained variation. RESULTS: Seven hundred and six patients were recruited between 2011 and 2014 and RCC confirmed in 608 (86%) patients. Application of the Leibovich score to patients with localized clear cell RCC in this contemporary cohort demonstrated good model discrimination (c-index = 0.77) but suboptimal calibration, with improved MFS for intermediate- and high-risk patients (5-year MFS 85% and 50%, respectively) compared to the original Leibovich cohort (74% and 31%) and a historic (1998-2006) UK cohort (76% and 37%). The proportion of variation in outcome explained by the model is low and has declined over time (28% historic vs 22% contemporary UK cohort). CONCLUSION: Prognostic models are widely employed in patients with localized RCC to guide surveillance intensity and clinical trial selection. However, the majority of the variation in outcome remains unexplained by the Leibovich model and, over time, MFS rates among intermediate- and high-risk classified patients have altered. These findings are likely to have implications for all such models used in this setting.

Somatic Transformation in Metastatic Testicular Germ Cell Tumours - A Different Disease Entity.

BACKGROUND/AIM: The occurrence of somatic transformation in germ cell tumour (GCT) is rare, with increased incidence in teratomatous tumours. The aim of this study was to understand the clinical outcomes of patients with metastatic GCT with somatic transformation. MATERIALS AND METHODS: A retrospective study was conducted in two tertiary cancer centres in London. Between 1998 and 2016, 30 cases of somatic transformation in GCT treated at the Mount Vernon Cancer Centre and St. Bartholomew's Hospital were identified. The median age at diagnosis was 34 years (range=18-56 years). The histological diagnosis at transformation was rhabdomyosarcoma, sarcomatoid yolk sac, sarcoma (non-specified), clear cell carcinoma, adenocarcinoma and primitive neuro ectodermal tumour (PNET). RESULTS: The 5-year survival rate of all patients was 47%, and that of patients with testicular primary (n=26 patients) was 37%. CONCLUSION: Somatic transformation component in testicular GCTs is generally considered to be an adverse prognostic factor, however, a reasonable 5-year overall survival rate (87.5%) was observed in patients who present with this at first diagnosis.

Massive seminoma presenting with inguinal lymph node metastases only.

Seminomatous germ cell tumours characteristically affect men in their second-to-fourth decades, presenting as a testicular mass. Metastases when present are usually seen in para-aortic lymph nodes. These tumours are difficult to diagnose clinically and histologically when the presentation is unusual. We describe a seminoma presenting in a 61-year-old male as an inguinal mass with associated lymphadenopathy resembling lymphoma. Past medical history included ipsilateral cryptorchidism and orchidopexy. The tumour responded well to conventional chemotherapy.This case illustrates a possible diagnostic pitfall and that germ cell tumours should be included in the differential diagnosis of tumours presenting in the groin.

Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution.

BACKGROUND: Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. RESULTS: We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. CONCLUSIONS: In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.

Tumour-to-tumour metastases: prostate carcinoma metastasising to a renal oncocytoma.

This is a case report of prostate carcinoma metastasising to a renal oncocytoma. The report demonstrates the unusual presentation of metastases from a common cancer to a common benign tumour, and reviews the rare phenomenon of tumour-to-tumour metastases.

The role of laparoscopy and robotic surgery in the management of small renal masses.

Increased utilization of cross-sectional abdominal imaging has led to a significant increase in the incidence of small renal masses. There is a growing body of literature suggesting that these lesions have a low malignant potential, thus supporting surveillance as a therapeutic option, particularly in the elderly population. Over the last decade, there has been an explosion of minimally invasive techniques for managing these lesions, including laparoscopic nephrectomy, laparoscopic partial nephrectomy, cryotherapy, radiofrequency ablation and, more recently, robotic-assisted surgery. The aim of this article is to review recent literature and assess the role of laparoscopic and robotic-assisted surgery in the management of small renal masses.

Lymphoepithelioma-like carcinoma of the urinary bladder: A case report and review of systemic treatment options.

Lymphoepithelioma-like carcinoma (LELC) of the urinary bladder is a rare variant, which can occur in a pure form or in conjunction with transitional cell carcinoma. Owing to the scarcity of reported cases, the optimum treatment is yet to be defined, although the benefits of chemotherapy are increasingly recognised. We present a case of a 64-year-old man with pure LELC, treated with trans-urethral resection of the bladder tumor (TURBT) and primary gemcitabine and platinum-based chemotherapy. He remained free of disease at six-month follow-up cystoscopy. The case adds to the growing evidence for the efficacy of chemotherapy, coupled with TUR, as part of a bladder-preserving treatment option for LELC.

Systematic review of internal hernia formation following laparoscopic left nephrectomy.

This is the first identifiable description where internal herniation following laparoscopic left nephrectomy necessitated gangrenous small intestinal resection; similar cases and prevention are discussed.

Perirenal schwannoma: a case report.

INTRODUCTION: Nerve sheath tumours of the kidney are particularly rare and, in the few reported cases, are all situated in the hilar region. CASE PRESENTATION: We describe the case of a tumour presenting towards the lateral border of the ventral aspect of the mid-zone of the kidney. This was a spindle cell lesion in which the cells strongly and diffusely expressed cytokeratins, but were negative for epithelial membrane antigen. The cells also expressed S-100 protein and glial fibrillary acidic protein, confirming the diagnosis of a cellular schwannoma. CONCLUSION: To the best of our knowledge, this is the first case of a cellular schwannoma presenting towards the lateral border of the kidney. The case also highlights the importance of using a panel of antibodies in diagnosing spindle cell neoplasms in the kidney.

Therapy insight: prophylaxis, monitoring and treatment of perioperative myocardial ischemia with emphasis on urological surgery.

Unrecognized or silent perioperative myocardial ischemia is common in patients who undergo high-risk surgery, including cystectomy, and could predict cardiac morbidity and mortality in postoperative patients. This disorder is not merely a marker of extensive coronary disease but has a close association with perioperative myocardial infarction (PMI). In a review of published data, including meta-analyses, in the context of high-risk urological surgery, up to 50% of PMIs were found to go unrecognized if only clinical signs and symptoms are considered. Prevention and treatment of these previously unrecognized cardiac events might significantly reduce long-term morbidity and mortality. The emergence of reliable markers of PMI, such as increased levels of troponin I, could help in the detection of events that would have otherwise remained unnoticed. In this Review we examine the effect of these developments in the context of high-risk urological surgery. Changes to preoperative assessment, perioperative management, and prophylaxis of PMI are critically assessed. We performed a prospective audit using postoperative troponin I levels to assess the rate of silent perioperative myocardial ischemia and infarction. An increasingly proactive attitude towards perioperative monitoring for myocardial ischemia and infarction has evolved, and postoperative serial screening with troponin I might be beneficial in high-risk patients undergoing major urological surgery.