Tim O'Brien

Regulation of E-cadherin Expression by VHL and Hypoxia-Inducible Factor

Mutations in von Hippel-Lindau tumor suppressor gene (VHL) underlie the VHL hereditary cancer syndrome and also occur in most sporadic clear cell renal cell cancers (CCRCC). Currently, the mechanism(s) by which VHL loss of function promotes tumor development in the kidney are not fully elucidated. Here, we show that VHL inactivation in precancerous lesions in kidneys from patients with VHL disease correlates with marked down-regulation of the intercellular adhesion molecule E-cadherin. Moreover, in VHL-defective cell lines (RCC4 and RCC10) derived from sporadic CCRCC, reexpression of VHL was found to restore E-cadherin expression. The product of the VHL gene has multiple reported functions, the best characterized of which is its role as the recognition component of an ubiquitin E3 ligase complex responsible for mediating oxygen-dependent destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits. We show that HIF activation is necessary and sufficient to suppress E-cadherin in renal cancer cells. Given the fundamental role of E-cadherin in controlling epithelial behavior, our findings give insight into how VHL inactivation/HIF activation may lead to kidney cancer and also indicate a mechanism by which reduced oxygenation could alter E-cadherin expression in other cancers and influence normal homeostasis in other epithelia.

Robotic-assisted Laparoscopic Radical Cystectomy with Extracorporeal Urinary Diversion: Initial Experience

BACKGROUND The use of robotic technology for laparoscopic prostatectomy is now well established. The same cannot yet be said of robotic-assisted laparoscopic radical cystectomy (RARC), which is performed in just a few centres worldwide. OBJECTIVE We present our technique and experience of this procedure using the da Vinci surgical system. DESIGN, SETTING, AND PARTICIPANTS From 2004 to 2007, 23 patients underwent RARC and urinary diversion at our institution. SURGICAL PROCEDURE We report the development of our technique for RARC, which involves posterior dissection, lateral pedicle control, anterior dissection, and lymphadenectomy prior to either ileal conduit urinary diversion or Studer pouch reconstruction performed extracorporeally. MEASUREMENTS Demographic and perioperative data were recorded prospectively. Oncologic and functional outcomes were assessed at 3- to 6-mo intervals. RESULTS AND LIMITATIONS To date, 23 patients have undergone this procedure at our institution. Of those, 19 had ileal loop urinary diversion and 4 were suitable for Studer pouch reconstruction. Mean total operative time plus or minus (+/-) standard deviation (SD) was 397+/-83.8min. Mean blood loss +/-SD was 278+/-229ml with one patient requiring a blood transfusion. Surgical margins were clear in all patients with a median +/-SD of 16+/-8.9 lymph nodes retrieved. The complication rate was 26%. At a mean follow-up +/-SD of 17+/-13 (range 4-40) mo, one patient had died of metastatic disease and one other is alive with metastases. The remaining 21 patients are alive without recurrence. CONCLUSIONS RARC remains a procedure in evolution in the small number of centres carrying out this type of surgery. Our initial experience confirms that it is feasible with acceptable morbidity and good short-term oncologic results.

Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial).

BACKGROUND Standard treatment for upper urinary tract urothelial carcinoma (UUTUC) is nephroureterectomy. Subsequently, around 40% of patients will develop a bladder tumour potentially because of implantation from the primary tumour. OBJECTIVE To prevent bladder tumour after nephroureterectomy with a single postoperative dose of intravesical mitomycin C (MMC). DESIGN, SETTING, AND PARTICIPANTS A prospective, randomised, nonblinded trial (ODMIT-C: One Dose Mitomycin C) was undertaken in 46 British centres between July 2000 and December 2006. The study recruited 284 patients with no previous or concurrent history of bladder cancer undergoing nephroureterectomy for suspected UUTUC. INTERVENTION A single postoperative intravesical dose of MMC (40 mg in 40 ml saline) or standard management on removal of the urinary catheter. MEASUREMENTS Bladder tumour formation was judged by visual appearance at cystoscopy at 3, 6, and 12 mo following nephroureterectomy. RESULTS AND LIMITATIONS One hundred forty-four patients were randomised to receive MMC and 140 patients to receive standard care. In the MMC arm, 105 of 144 patients (73%) and 115 of 140 patients (82%) in the standard care arm received their allocated treatment. Thirteen of 105 patients who received MMC and 20 of 115 patients allocated to standard treatment did not complete follow-up. By modified intention-to-treat analysis, 21 of 120 patients (17%) in the MMC arm developed a bladder recurrence in the first year compared to 32 of 119 patients (27%) in the standard treatment arm (p=0.055). By treatment as per protocol analysis, 17 of 105 patients (16%) in the MMC arm and 31 of 115 patients (27%) in the standard treatment arm developed a recurrence (p=0.03). No serious adverse events were reported. A limitation is that histologic proof of recurrence was not required in this trial. CONCLUSIONS A single postoperative dose of intravesical MMC appears to reduce the risk of a bladder tumour within the first year following nephroureterectomy for UUTUC. The absolute reduction in risk is 11%, the relative reduction in risk is 40%, and the number needed to treat to prevent one bladder tumour is nine.

The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer

BACKGROUND The role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma (ccRCC) is controversial. OBJECTIVE To determine the outcome of patients with metastatic ccRCC who receive sunitinib prior to planned nephrectomy. DESIGN, SETTING, AND PARTICIPANTS The study combined the data from two prospective phase 2 studies that assessed upfront sunitinib (12-16 wk) prior to nephrectomy in previously untreated patients with metastatic renal cell carcinoma (RCC). Sunitinib was discontinued during the perioperative period (median: 29 d). INTERVENTION Sunitinib 50mg in six weekly cycles (4 wk on, 2 wk off). MEASUREMENTS Progression-free (PFS) and overall survival (OS) using the Kaplan-Meier method. RESULTS AND LIMITATIONS Twenty-one patients (32%) had Memorial Sloan-Kettering Cancer Centre (MSKCC) poor-risk disease; 45 (68%) had intermediate-risk disease. Nephrectomy was not performed in 19 (29%), most commonly due to disease progression (n = 12). The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1-8.5). Seventeen (36%) patients progressed during the treatment break, 13 (76%) of whom stabilised upon reinitiating of sunitinib. The OS for the cohort was 15.2 mo (95% CI, 10.3-NA). The OS for the intermediate MSKCC risk group was significantly longer than that for the poor-risk group (26.0 mo [95% CI, 13.6-NA] and 9.0 mo [95% CI, 5.8-20.5], respectively; p < 0.01). In multivariate analysis, progression of disease prior to planned nephrectomy (hazard ratio [HR]: 5.34; 95% CI, 3.17-13.27), high Fuhrman grade (HR 3.27; 95% CI, 1.38-7.72), and MSKCC poor risk at diagnosis (HR 4.75; 95% CI, 2.05-11.02) were associated with short survival (p < 0.01). However, in the absence of randomised studies it is not possible to determine if this approach is beneficial. CONCLUSIONS Upfront sunitinib prior to planned nephrectomy in intermediate-risk disease is associated with a median survival of >2 yr despite frequent progression during treatment break. Progression in metastatic sites prior to planned surgery and MSKCC poor-risk disease was associated with a poor outcome.

Long-term Outcomes of Robot-assisted Radical Cystectomy for Bladder Cancer

BACKGROUND Long-term oncologic and functional outcomes after robot-assisted radical cystectomy (RARC) for bladder cancer (BCa) are lacking. OBJECTIVE To report oncologic and functional outcomes in a cohort of patients who have completed a minimum of 5 yr and a maximum of 8 yr of follow-up after RARC and extracorporeal urinary diversion. DESIGN, SETTING, AND PARTICIPANTS In this paper, we report on the experience from one of the first European urology centres to introduce RARC. Only patients between 2004 and 2006 were included to ensure follow-up of ≥ 5 yr. We report on an analysis of oncologic outcomes in 14 patients (11 males and 3 females) with muscle-invasive/high-grade non-muscle-invasive or bacillus Calmette-Guérin-refractory carcinoma in situ who opted to have RARC. INTERVENTION RARC with pelvic lymphadenectomy was performed using the three-arm standard da Vinci Surgical System (Intuitive Surgical, CA, USA). Urinary diversion, either ileal conduit (n=12) or orthotopic neobladder (n=2), was constructed extracorporeally. OUTCOME MEASUREMENTS Parameters were recorded in a prospectively maintained database including assessment of renal function, overall survival, disease-specific survival, development of metastases, and functional outcomes. STATISTICAL ANALYSIS Results were analysed using descriptive statistical analysis. Survival data were analysed and presented using the Kaplan-Meier survival curve. RESULTS AND LIMITATIONS Five of the 14 patients have died. Three patients died of metastatic disease, and two died of unrelated causes. Two other patients are alive with metastases, and another has developed primary lung cancer. Six patients are alive and disease-free. These results show overall survival of 64%, disease-specific survival of 75%, and disease-free survival of 50%. None of the patients had deterioration of renal function necessitating renal replacement therapy. Three of four previously potent patients having nerve-sparing RARC recovered erectile function. The study is limited by the relatively small number of highly selected patients undergoing RARC, which was a novel technique 8 yr ago. The standard da Vinci Surgical System made extended lymphadenectomy difficult. CONCLUSIONS Within limitations, in our experience RARC achieved excellent control of local disease, but the outcomes in patients with metastatic disease seem to be equivalent to the outcomes of open radical cystectomy.

Role of fluorodeoxyglucose positron emission tomography (FDG PET)-computed tomography (CT) in the staging of bladder cancer

To determine whether to use 18F‐fluorodeoxyglucose positron emission tomography (FDG PET) scans in the preoperative staging of bladder cancer (BC).

Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.

Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette‐Guérin

Study Type – Diagnosis (case series) Level of Evidence 4

Open partial nephrectomy: outcomes from two UK centres

To define the current achievable outcomes from open partial nephrectomy (OPN) in the UK at a time when other treatments for small kidney tumours are increasingly being advocated. Current knowledge of the effectiveness of OPN is limited by the fact that published data are almost exclusively derived from a very few centres of established world renown.

Outpatient laser ablation of non‐muscle‐invasive bladder cancer: is it safe, tolerable and cost‐effective?

To evaluate the safety, tolerability and effectiveness of outpatient (office‐based) laser ablation (OLA), with local anaesthetic, for non‐muscle‐invasive bladder cancer (NMIBC) in an elderly population with and without photodynamic diagnosis (PDD). To compare the cost‐effectiveness of OLA of NMIBC with that of inpatient cystodiathermy (IC).