Rajan Veeratterapillay

Side Population in Human Non-Muscle Invasive Bladder Cancer Enriches for Cancer Stem Cells That Are Maintained by MAPK Signalling

Side population (SP) and ABC transporter expression enrich for stem cells in numerous tissues. We explored if this phenotype characterised human bladder cancer stem cells (CSCs) and attempted to identify regulatory mechanisms. Focusing on non-muscle invasive bladder cancer (NMIBC), multiple human cell lines were used to characterise SP and ABC transporter expression. In vitro and in vivo phenotypic and functional assessments of CSC behaviour were undertaken. Expression of putative CSC marker ABCG2 was assessed in clinical NMIBC samples (n = 148), and a role for MAPK signalling, a central mechanism of bladder tumourigenesis, was investigated. Results showed that the ABCG2 transporter was predominantly expressed and was up-regulated in the SP fraction by 3-fold (ABCG2hi) relative to the non-SP (NSP) fraction (ABCG2low). ABCG2hi SP cells displayed enrichment of stem cell markers (Nanog, Notch1 and SOX2) and a three-fold increase in colony forming efficiency (CFE) in comparison to ABCG2low NSP cells. In vivo, ABCG2hi SP cells enriched for tumour growth compared with ABCG2low NSP cells, consistent with CSCs. pERK was constitutively active in ABCG2hi SP cells and MEK inhibition also inhibited the ABCG2hi SP phenotype and significantly suppressed CFE. Furthermore, on examining clinical NMIBC samples, ABCG2 expression correlated with increased recurrence and decreased progression free survival. Additionally, pERK expression also correlated with decreased progression free survival, whilst a positive correlation was further demonstrated between ABCG2 and pERK expression. In conclusion, we confirm ABCG2hi SP enriches for CSCs in human NMIBC and MAPK/ERK pathway is a suitable therapeutic target.

Organ‐preserving surgery for penile cancer: description of techniques and surgical outcomes

Study Type – Therapy (case series)

Long-term effect of urethral dilatation and internal urethrotomy for urethral strictures.

Purpose of review Urethral dilatation and direct visual internal urethrotomy (DVIU) are widely used minimally invasive options to manage men with urethral strictures. Advances in open urethroplasty with better long-term cure rates have fuelled the continuing debate as to which treatment is best for primary and recurrent urethral strictures. We reviewed recent literature to identify contemporary practice of urethral dilatation and DVIU and the long-term outcome of these procedures. Recent findings Systematic literature search for the period January 2010 to December 2011 showed that urethral dilatation and DVIU remain frequently used treatment options as confirmed by surveys of urologists in the USA and the Netherlands. Multiple reports of laser DVIU confirm the safety of this approach but long-term data were lacking. Stricture free rates from urethra dilatation and DVIU vary from 10 to 90% at 12 months, although adjunctive intermittent self-dilatation can reduce time to recurrence. Although quality-of-life benefit appears good in the short term, repeated procedures may harm sexual function in the long-term. Summary Urethral dilatation and DVIU remain widely used in urethral stricture management but high-level comparative evidence of benefit and harms against urethroplasty in the short and long-term is still lacking.

Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor overactivity

To report discontinuation rates, inter‐injection interval and complication rates after repeated intravesical botulinum toxin type A for the treatment of detrusor overactivity.

Reconstructing the lower urinary tract: The Mitrofanoff principle

Since the original description of the trans-appendicular continent cystostomy by Mitrofanoff in 1980, a variety of techniques have been described for creating a continent catheterisable channel leading to the bladder, which avoids the native urethra. The Mitrofanoff principle involves the creation of a conduit going into a low pressure reservoir, which can emptied through clean intermittent catheterization through an easily accessible stoma. A variety of tissue segments have been used for creating the conduit, but the two popular options in current urological practice remain the appendix and Yang-Monti transverse ileal tube. The Mitrofanoff procedure has an early reoperation rate for bleeding, bowel obstruction, anastomotic leak or conduit breakdown of up to 8% and the most common long-term complication noted is stomal stenosis resulting in difficulty catheterizing the conduit. However, in both pediatric and adult setting, reports imply that the procedure is durable although it is associated with an overall re-operation rate of up to 32% in contemporary series. Initial reports of laparoscopic and robotic-assisted Mitrofanoff procedures are encouraging, but long-term outcomes are still awaited.

Accuracy of the revised 2010 TNM classification in predicting the prognosis of patients treated for renal cell cancer in the north east of England

Background The TNM classification for renal cell cancer (RCC) should accurately predict and assign prognostic information for patients. In this study the recent 2010 revision to the TNM classification was compared with the previous 2002 classification with regard to survival outcomes. Methods All patients having radical nephrectomy for RCC in the 5-year period 2004–8 at a tertiary referral centre were included. Pathological and radiological records were reviewed to identify TNM stage (2002 and 2010 classification) and survival data were captured. Results 345 patients with RCC were identified. Based on the 2002 TNM staging system and using outcomes in T1 staged tumours as a baseline, statistically significant differences in disease-specific survival were noted between patients with T1 and T3b tumours (log rank p<0.001) but not between those with T1 and T3a tumours (p=0.33). However, when tumour stage was reassigned according to the 2010 classification, patients with T3a tumours were also found to do statistically worse than T1 staged disease (p<0.001). Conclusion In our cohort, the new 2010 TNM reclassification of T3 tumours showed better correlation with predicting worsening outcomes compared with localised disease.

Augmentation cystoplasty: Contemporary indications, techniques and complications

Augmentation cystoplasty (AC) has traditionally been used in the treatment of the low capacity, poorly compliant or refractory overactive bladder (OAB). The use of intravesical botulinum toxin and sacral neuromodulation in detrusor overactivity has reduced the number of AC performed for this indication. However, AC remains important in the pediatric and renal transplant setting and still remains a viable option for refractory OAB. Advances in surgical technique have seen the development of both laparoscopic and robotic augmentation cystoplasty. A variety of intestinal segments can be used although ileocystoplasty remains the most common performed procedure. Early complications include thromboembolism and mortality, whereas long-term problems include metabolic disturbance, bacteriuria, urinary tract stones, incontinence, perforation, the need for intermittent self-catheterization and carcinoma. This article examines the contemporary indications, published results and possible future directions for augmentation cystoplasty.

Hematuria secondary to benign prostatic hyperplasia: retrospective analysis of 166 men identified in a single one stop hematuria clinic.

Introduction: Hematuria secondary to benign prostatic hyperplasia (BPH) can occur due to a vascular primary gland itself or due to the vascular re-growth of the prostate following a transurethral resection of the prostate (TURP). We aim to evaluate the clinical presentation and management in patients within both these groups. Materials and Methods: We retrospectively archived the data of 166 men diagnosed with hematuria secondary to BPH from our hematuria clinic database from March 2003 and March 2006. The 166 patients were divided into 2 groups: Group I (n = 94) hematuria with no previous TURP; Group II (n = 72) hematuria with previous TURP. The clinical management in both groups included reassurance, commencement of a 5-alpha reductase inhibitor (finasteride) or a primary TURP in Group I or re-do TURP in Group II. Results: The median age was 73 years (range 45–94 years) for both groups. Outcomes combined for both groups included: reassurance alone in 26% (n = 43), finasteride in 51% (n = 84) and TURP in 12% (n = 19). Patients managed with reassurance alone or TURP had no further episodes of hematuria. At a mean follow-up was 18 months (range 7–22 months), 2 patients treated with finasteride re-bled but did require further intervention. A further 2 men elected to stop finasteride due to erectile dysfunction and gynecomastia respectively. Conclusion: BPH can present with hematuria. Following re-evaluation in a hematuria clinic, the lack of any subsequent cancer diagnosis in these patients suggests that repeat hematuria investigations should be carefully re-considered.

Benefits and Harms of Treatment of Asymptomatic Bacteriuria: A Systematic Review and Meta-analysis by the European Association of Urology Urological Infection Guidelines Panel

People with asymptomatic bacteriuria (ABU) are often unnecessarily treated with antibiotics risking adverse effects and antimicrobial resistance. We performed a systematic review to determine any benefits and harms of treating ABU in particular patient groups. Relevant databases were searched and eligible trials were assessed for risk-of-bias and Grading of Recommendations, Assessment, Development and Education quality. Where possible, a meta-analysis of extracted data was performed or a narrative synthesis of the evidence was presented. After screening 3626 articles, 50 studies involving 7088 patients were included. Overall, quality of evidence ranged from very low to low. There was no evidence of benefit for patients with no risk factors, patients with diabetes mellitus, postmenopausal women, elderly institutionalised patients, patients with renal transplants, or patients prior to joint replacement, and treatment was harmful for patients with recurrent urinary tract infection (UTI). Treatment of ABU resulted in a lower risk of postoperative UTI after transurethral resection surgery. In pregnant women, we found evidence that treatment of ABU decreased risk of symptomatic UTI, low birthweight, and preterm delivery. ABU should be treated prior to transurethral resection surgery. In addition, current evidence also suggests that ABU treatment is required in pregnant women, although the results of a recent trial have challenged this view. PATIENT SUMMARY We reviewed available scientific studies to see if people with bacteria in their urine but without symptoms of urinary tract infection should be treated with antibiotics to eliminate bacteria. For most people, treatment was not beneficial and may be harmful. Antibiotic treatment did appear to benefit women in pregnancy and those about to undergo urological surgery.

Oncologic Outcomes of Penile Cancer Treatment at a UK Supraregional Center

OBJECTIVE To report contemporary treatment outcomes of penile squamous cell carcinoma at a UK supraregional center, including patterns of therapy, oncologic results, and long-term survival. PATIENTS AND METHODS Patients with squamous cell carcinoma treated during the period January 2000 to January 2011 were included. Records were reviewed to identify the mode of therapy (penile preserving or amputative surgery), pathology reports (reclassified according to the 2009 tumor-nodes-metastasis classification), recurrence patterns, and cancer-specific survival (CSS). Kaplan-Meier plots were used for survival analyses. RESULTS Two hundred three patients were identified with a median follow-up of 61 months. At presentation, 165 patients (82%) were node negative, 31 (15%) were node positive, and 7 (3%) had metastatic disease. Management was penile preserving surgery (n = 99, 49%), partial penectomy (n = 49, 24%), radical penectomy (n = 48, 24%), and chemotherapy or radiotherapy for metastatic disease (n = 7, 3%). After organ-preserving surgery, the local recurrence rate was 18% (compared with 4% for amputative surgery), with 94% of recurrences occurring within 3 years. Histopathologic staging was as follows, with pTis (20%), pT1 (27%), pT2 (27%), pT3 (7%), and pT4 (1%). Kaplan-Meier analysis showed a 5-year CSS of 85% and a 10-year CSS of 81%. Five-year CSS was noted to decrease with advancing stage with pN0 tumors (92%), N1 (73%), N2 (61%), N3 (33%), and M1 (0%; P <.0001). CONCLUSION Supraregional penile cancer management has led to considerable clinical experience in our center over the past decade. Close follow-up is vital to pick up local recurrence after penile-preserving surgery. Overall oncologic outcomes are good with a 5-year CSS of 85%.