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1.  The impact of method of distal ureter management during radical nephroureterectomy on tumour recurrence 
Canadian Urological Association Journal  2014;8(11-12):E845-E852.
Radical nephroureterectomy for upper tract urothelial carcinoma (UTUC) must include some form of distal ureter management to avoid high rates of tumour recurrence. It is uncertain which distal ureter management technique has the best oncologic outcomes. To determine which distal ureter management technique resulted in the lowest tumour recurrence rate, we analyzed a multi-institutional Canadian radical nephroureterectomy database.
We retrospectively analyzed patients who underwent radical nephroureterectomy with distal ureter management for UTUC between January 1990 and June 2010 at 10 Canadian tertiary hospitals. Distal ureter management approaches were divided into 3 categories: (1) extravesical tenting for ureteric excision without cystotomy (EXTRAVESICAL); (2) open cystotomy with intravesical bladder cuff excision (INTRAVESICAL); and (3) extravesical excision with endoscopic management of ureteric orifice (ENDOSCOPIC). Data available for each patient included demographic details, distal ureter management approach, pathology and operative details, as well as the presence and location of local or distant recurrence. Clinical outcomes included overall recurrence-free survival and intravesical recurrence-free survival. Survival analysis was performed with the Kaplan-Meier method. Multivariable Cox regression analysis was also performed.
A total of 820 patients underwent radical nephroureterectomy with a specified distal ureter management approach at 10 Canadian academic institutions. The mean patient age was 69.6 years and the median follow-up was 24.6 months. Of the 820 patients, 406 (49.5%) underwent INTRAVESICAL, 316 (38.5%) underwent EXTRAVESICAL, and 98 (11.9%) underwent ENDOSOPIC distal ureter management. Groups differed significantly in their proportion of females, proportion of laparoscopic cases, presence of carcinoma in situ and pathological tumour stage (p < 0.05). Recurrence-free survival at 5 years was 46.3%, 35.6%, and 30.1% for INTRAVESICAL, EXTRAVESICAL and ENDOSCOPIC, respectively (p < 0.05). Multivariable Cox regression analysis confirmed that INTRAVESICAL resulted in a lower hazard of recurrence compared to EXTRAVESICAL and ENDOSCOPIC. When looking only at intravesical recurrence-free survival (iRFS), a similar trend held up with INTRAVESICAL having the highest iRFS, followed by ENDOSCOPIC and then EXTRAVESICAL management (p < 0.05). At last follow-up, 406 (49.5%) patients were alive and free of disease.
Open intravesical excision of the distal ureter (INTRAVESICAL) during radical nephroureterectomy was associated with improved overall and intravesical recurrence-free survival compared with extravesical and endoscopic approaches. These findings suggest that INTRAVESICAL should be considered the gold standard oncologic approach to distal ureter management during radical nephroureterectomy. Limitations of this study include its retrospective design, heterogeneous cohort, and limited follow-up.
PMCID: PMC4250251  PMID: 25485014
2.  Optimizing a frail elderly patient for radical cystectomy with a prehabilitation program 
Canadian Urological Association Journal  2014;8(11-12):E884-E887.
The purpose of this case report is to discuss the positive impact of a multimodal prehabilitation program on postoperative recovery of a frail patient undergoing radical cystectomy. An 85-year-old man with significant history for poorly controlled type II diabetes, anemia, chronic renal failure, and glaucoma was found to have muscle invasive urothelial carcinoma of the bladder with hydronephrosis. He was scheduled for elective radical cystoprostatectomy and ileal conduit diversion. He was enrolled in a multimodal prehabilitation program in view of his frailty (Fried score = 5), 15% body weight loss, weak grip strength, severe depression and moderate anxiety, poor nutritional status (patient-generated subjective global assessment [PG-SGA] = B), low functional walking capacity (6-minute walking test [6MWT] = 210 metres, predicted 621 metres). The 4-week program included moderate aerobic and resistant exercises, nutritional counselling with whey protein supplementation (20 g/day), and relaxation exercises. Surgery and the postoperative period were uneventful, although he required treatment of his hyperglycemia and hypomagnesemia. He left the hospital on postoperative day 7 and returned home where he continued the multimodal program for 8 weeks. Measurements of 6MWT, Health-Related Quality of Life (SF-36), physical activity, Hospital Anxiety and Depression Scale (HADS), were conducted at baseline, before surgery and at 4 and 8 weeks after surgery. These tests revealed a progressive remarkable improvement before surgery that continued after surgery.
PMCID: PMC4250260  PMID: 25485023
3.  Enhanced recovery pathway for radical prostatectomy: Implementation and evaluation in a universal healthcare system 
Enhanced recovery pathways are standardized, multidisciplinary, consensus-based tools that provide guidelines for evidence-based decision-making. This study evaluates the impact of the implementation of a clinical care pathway on patient outcomes following radical prostatectomy in a universal healthcare system.
Medical charts of 200 patients with prostate cancer who underwent open and minimally invasive radical prostatectomy at a single academic hospital from 2009 to 2012 were reviewed. A group of 100 consecutive patients’ pre-pathway implementation was compared with 99 consecutive patients’ post-pathway implementation. Duration of hospital stay, complications, post-discharge emergency department visits and readmissions were compared between the 2 groups.
Length of hospital stay decreased from a median of 3 (inter-quartile range [IQR] 4 to 3 days) days in the pre-pathway group to a median of 2 (IQR 3 to 2 days) days in the post-pathway group regardless of surgical approach (p < 0.0001). Complication rates, emergency department visits and hospital readmissions were not significantly different in the pre- and post-pathway groups (17% vs. 21%, p = 0.80; 12% vs. 12%, p = 0.95; and 3% vs. 7%, p = 0.18, respectively). These findings were consistent after stratification by surgical approach. Limitations of our study include lack of assessment of patient satisfaction, and the retrospective study design.
The implementation of a standardized, multidisciplinary clinical care pathway for patients undergoing radical prostatectomy improved efficiency without increasing complication rates or hospital readmissions.
PMCID: PMC4277521  PMID: 25553155
4.  First case of invasive squamous cell carcinoma in a stoma of a Monti ileovesicostomy 
Canadian Urological Association Journal  2014;8(9-10):E654-E656.
We report a very rare case of invasive squamous cell carcinoma (SCC) in the abdominal stoma of a Monti ileovesicostomy. Our patient underwent an uncomplicated Monti ileovesicostomy at age 16 for a neurogenic bladder. She presented 10 years later with difficulty catheterizing the stoma. A biopsy of peristomal tissue showed moderately differentiated SCC. A cystoscopy did not reveal any bladder tumours or suspicious lesions. A computed tomography (CT) scan of the abdomen and pelvis did not demonstrate metastasis. The patient underwent a complete en bloc resection of the stomal site, the Monti, a partial cuff of bladder, and 2 loops of bowel that were adherent to the Monti. Final pathology revealed pure invasive SCC arising around the stoma and negative surgical margins. Six months later, a follow-up CT scan showed no evidence of malignancy, while a cystoscopy revealed a small erythematous area in the posterior bladder wall. Urinary cytology was positive for SCC. Transurethral resection of the erythematous lesion with random bladder biopsies showed SCC in situ in the erythematous lesion and right lateral bladder wall. Staging workup was negative. The patient subsequently underwent a radical cystectomy and ileal conduit diversion with bilateral pelvic lymph node dissection. Final pathology on cystectomy specimen was SCC in situ without evidence of invasive carcinoma. The patient has remained in remission at the 3-year follow-up.
PMCID: PMC4164558  PMID: 25295141
5.  Postoperative mortality and complications after radical cystectomy for bladder cancer in Quebec: A population-based analysis during the years 2000–2009 
Radical cystectomy (RC) is a very complex urologic procedure. Despite improvements in practice, technique and process of care, it is still associated with significant complications, including death, with reported postoperative mortality rates ranging from 0.8% to 8%. We examine the quality of surgical care indicators and document the mortality rates at 30, 60 and 90 days after RC across Quebec.
Within the Régie de l’assurance maladie du Québec (RAMQ) administrative database (this database provides prospectively collected universal data on all medical services) and the Institut de la statistique du Québec (ISQ) database (this provides vital status data), we used procedure codes to identify patients who underwent RC for bladder cancer in Quebec over 10 years (between 2000 and 2009), as well as RC outcomes and dates of death. Data obtained were retrospectively analyzed in relation to multiple parameters, including patient characteristics and health-care providers’ volumes. The outcomes analyzed included postoperative complications and mortality rates at 30, 60 and 90 days.
A total of 2778 RC were performed in 48 hospitals by 122 urologists across Quebec. Among them, 851 (30.6%) patients had at least one postoperative complication and 350 (12.6%) patients had more than one complication. The overall mortality rates at 30, 60 and 90 days were 2.8%, 5.3% and 7.5%, respectively, with significantly elevated 90-day mortality rates in some centres. In the multivariate analysis, increased age was associated with increased risk of post-RC complications and mortality. For example, patients over 75 had more chance of having at least one postoperative complication (odds ratio [OR] 1.66, 95% confidence interval [CI]: 1.31–2.11) and mortality at 90 days (OR 3.28, 95% CI: 2.05–5.26). Provider volume effect on outcomes was statistically significant, with large hospitals having decreased risk of 30-day mortality (OR 0.29, 95% CI: 0.12–0.70), 60-day mortality (OR 0.41, 95% CI: 0.26–0.82) and 90-day mortality (OR 0.52, 95% CI: 0.29–0.93) when compared to smaller hospitals. Surgeon volume showed weak, but not statistically significant, evidence of reduced odds of mortality for the high-volume surgeon. Limitations to our study include reliance on administrative data, which lack some relevant clinical information (such as patient functional status and tumour pathological characteristics) to perform risk adjustment analysis.
Our study demonstrates that postoperative outcomes after RC in Quebec varies based on several parameters. In addition, 30-day postoperative mortality after RC in Quebec appears acceptable. However, 90-day postoperative mortality rates remain significantly elevated in some centres, particularly in the elderly. This requires further research.
PMCID: PMC4137011  PMID: 25210550
6.  Royal College surgical objectives of urologic training: A survey of faculty members from Canadian training programs 
According to the Royal College objectives of training in urology, urologic surgical procedures are divided as category A, B and C. We wanted to determine the level of proficiency required and achieved by urology training faculty for Royal College accreditation.
We conducted a survey that was sent electronically to all Canadian urology training faculty. Questions focused on demographics (i.e., years of practice, geographic location, subspecialty, access to robotic surgery), operating room contact with residents, opinion on the level of proficiency required from a list of 54 surgical procedures, and whether their most recent graduates attained category A proficiency in these procedures.
The response rate was 43.7% (95/217). Among respondents, 92.6% were full timers, 21.1% practiced urology for less than 5 years and 3.2% for more than 30 years. Responses from Quebec and Ontario formed 69.4% (34.7% each). Of the respondents, 37.9% were uro-oncologists and 75.7% reported having access to robotic surgery. Sixty percent of faculty members operate with R5 residents between 2 to 5 days per month. When respondents were asked which categories should be listed as category A, only 8 procedures received 100% agreement. Also, results varied significantly when analyzed by sub-specialty. For example, almost 50% or more of uro-oncologists believed that radical cystectomy, anterior pelvic exenteration and extended pelvic lymphadenectomy should not be category A. The following procedures had significant disagreement suggesting the need for re-classification: glanular hypospadias repair, boari flap, entero-vesical and vesicovaginal fistulae repair. Overall, more than 80% of faculty reported that their recent graduating residents had achieved category A proficiency, in a subset of procedures. However, more than 50% of all faculty either disagreed or were ambivalent that all of their graduating residents were Category A proficient in several procedures.
There is sufficient disagreement among Canadian urology faculty to suggest another revision of the current Royal College list of category A procedures.
PMCID: PMC4081244  PMID: 25024784
7.  Are Canadian urology residency programs fulfilling the Royal College expectations?: A survey of graduated chief residents 
We assess outgoing Canadian urology chief residents’ well-being, their satisfaction with their surgical training, and their proficiency in surgical procedures throughout their residency program.
In 2012 an anonymous survey was sent by email to all 29 graduated urology chief residents across Canada. The survey included a list of all urologic surgical procedures listed by the Royal College of Physicians and Surgeons of Canada (RCPSC). According to the A/B/C classification used to assess competence in these procedures (A most competent, C least competent), we asked chief residents to self-classify their competence with regards to each procedure and we compared the final results to the current RCPSC classification.
The overall response rate among chief residents surveyed was 97%. An overwhelming majority (96.4%) of residents agreed that the residency program has affected their overall well-being, as well as their relationships with their families and/or partners (67.8%). Overall, 85.7% agreed that research was an integral part of the residency program and 78.6% have enrolled in a fellowship program post-graduation. Respondents believed that they have received the least adequate training in robotic surgery (89.3%), followed by female urology (67.8%), andrology/sexual medicine/infertility (67.8%), and reconstructive urology (61.4%). Interestingly, in several of the 42 surgical procedures classified as category A by the RCPSC, a significant percentage of residents felt that their proficiency was not category A, including repair of urinary fistulae (82.1%), pediatric indirect hernia repair and meatal repair for glanular hypospadias (67.9%), open pyeloplasty (64.3%), anterior pelvic exenteration (61.6%), open varicocelectomy (60.7%) and radical cystoprostatectomy (33.3%). Furthermore, all respondents (100%) believed they were deficient in at least 1 of the 42 category A procedures, while 53.6 % believed they were deficient in at least 10 of the 42 procedures.
Most residents agree that their residency program has affected their overall well-being as well as their relationships with their families and/or partners. There is also a clear deficiency in what outgoing residents perceive they have achieved and what the RCPSC mandates. Future work should concentrate on addressing this discrepancy to assure that training and RCPSC expectations are better aligned.
PMCID: PMC4001631  PMID: 24839479
8.  Uptake of neoadjuvant chemotherapy for invasive bladder cancer 
PMCID: PMC4001665  PMID: 24839504
9.  Aldehyde dehydrogenase 1 expression in primary and metastatic renal cell carcinoma: an immunohistochemistry study 
ALDH1 has been shown to be a cancer stem cell marker, and its expression correlates with prognosis in a number of malignancies. We aimed to evaluate the expression of ALDH1 in a cohort of primary and metastatic RCC specimens, and to correlate expression with pathological outcomes such as tumor stage and grade, and clinical outcomes such as progression free survival.
Three tissue microarrays were constructed from 244 RCC specimens, taken from 1985 to 2006. Samples were stained using an ALDH1 monoclonal antibody and expression was quantified by degree of staining. Membrane and cytoplasm staining were considered separately. A retrospective chart review enabled correlation with clinical outcomes.
ALDH1 expression did not vary significantly based on tumor stage (P = 0.6274) or grade (P = 0.1666). ALDH1 showed significantly more membranous expression in clear cell RCC versus other subtypes (P < 0.0001), as well as in the primary setting compared to metastases (P = 0.0216). In terms of progression free survival, no significant differences were seen based on ALDH1 expression levels. In a subanalysis of clear cell tumors, ALDH1 membranous expression was decreased in tumors of higher stage (P = 0.0233).
ALDH1 may be useful in characterizing RCC tumors as clear cell subtype. However, unlike in other malignancies, ALDH1 may not be useful in prognosticating renal cancers. The clinical significance of decreased ALDH1 expression in the high stage and metastatic setting remains to be determined in further investigations.
PMCID: PMC3842840  PMID: 24266898
ALDH1; Renal cell carcinoma; Prognosis; Immunohistochemistry
10.  Regional differences in practice patterns and outcomes in patients treated with radical cystectomy in a universal healthcare system 
Canadian Urological Association Journal  2013;7(11-12):E667-E672.
Our objective is to assess differences in practice patterns and outcomes across 3 regions in bladder cancer patients treated with radical cystectomy under a universal healthcare system.
In total, we included 2287 patients treated with radical cystectomy at 8 Canadian centres from 1998 to 2008. Variables included various clinico-pathologic parameters, recurrence, and death stratified into different regions.
In total, 1105 patients were from the east region (group 1), 601 from the centre region (group 2), and 581 from the west region of Canada (group 3). The median follow-up of groups 1, 2, and 3 was 22.1, 17.1, and 28.6 months, respectively. Although the overall rate of neoadjuvant chemotherapy was low (3.1%), rates were higher in group 2 compared with groups 1 and 3 (p = 0.07). Continent diversions and extended lymphadenectomy were performed in 23.5%, 8.5%, 23.9% and 39.7%, 27.7%, 12.6% across groups 1, 2, and 3, respectively. There were statistically significant differences in gender distribution, performance of lymphadenectomy, presence of concomitant carcinoma in situ and lymphovascular invasion across the 3 groups. There were no differences among the 3 geographical locations in terms of stage, surgical margin status, and use of adjuvant chemotherapy. The mean number of days from the transurethral resection of the bladder tumour to cystectomy was 50, 79, 69 days for groups 1, 2, 3, respectively (p = 0.0006). The 5-year overall survival was 53.6%, 66.8%, and 52.4% for groups 1, 2 and 3, respectively (p < 0.0001).
Significant variations in practice patterns were noted across different geographic regions in a universal healthcare system. Use of continent diversions, extended lymphadenectomy, and neoadjuvant chemotherapy remains low across all 3 regions. Treatment delays are significant.
PMCID: PMC3840506  PMID: 24282454
11.  Does transperitoneal minimally invasive radical prostatectomy increase the amount of small bowel receiving salvage radiation? 
Transperitoneal minimally invasive radical prostatectomy (MIRP) has become first choice for several urologists and patients dealing with localized prostate cancer. We evaluate the effect of postoperative radiation on the small bowel in patients who underwent extraperitoneal open versus transperitoneal MIRP.
We reviewed all patients who received postoperative radiation from 2006 to 2010. Planning target volume (PTV) and surrounding organs, including the small bowel, were delineated. The presence of the small bowel in PTV and its volume in receiving each dose level were analyzed.
A total of 122 patients were included: 26 underwent MIRP and 96 underwent open prostatectomy. The median age of patients was 66 years, with median body mass index 27 kg/m2. The total PTV dose was 66 Gy, with the minimum and maximum doses received by the small bowel 0.4 and 66.4 Gy, respectively. The maximum volume of small bowel that received the safe limit of 40 Gy was 569 cm3. Of the 26 patients who underwent MIRP, 12 (46%) had small bowel identified inside the PTV compared to 57 (59%) among patients who underwent open prostatectomy (p = 0.228). The mean volume of the small bowel receiving 40 Gy was 26 and 67 cm3 in open and MIRP groups, respectively (p = 0.006); the incidence of acute complications was the same in both groups.
Higher volumes of the small bowel are subjected to significant radiation after MIRP procedures compared to open procedures; however, we could not demonstrate any impact on acute complications. Whether there is a difference in late complications remains to be evaluated.
PMCID: PMC3876447  PMID: 24381666
14.  Combining mTOR Inhibition with Radiation Improves Antitumor Activity in Bladder Cancer Cells In Vitro and In Vivo: A Novel Strategy for Treatment 
PLoS ONE  2013;8(6):e65257.
Radiation therapy for invasive bladder cancer allows for organ preservation but toxicity and local control remain problematic. As such, improving efficacy of treatment requires radiosensitization of tumor cells. The aim of study is to investigate if the mammalian Target of Rapamycin (mTOR), a downstream kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT survival pathway, may be a target for radiation sensitization.
Experimental Design
Clonogenic assays were performed using 6 bladder cancer cell lines (UM-UC3, UM-UC5, UM-UC6, KU7, 253J-BV, and 253-JP) in order to examine the effects of ionizing radiation (IR) alone and in combination with RAD001, an mTOR inhibitor. Cell cycle analysis was performed using flow cytometry. In vivo, athymic mice were subcutaneously injected with 2 bladder cancer cell lines. Treatment response with RAD001 (1.5 mg/kg, daily), fractionated IR (total 9Gy = 3Gy×3), and combination of RAD001 and IR was followed over 4 weeks. Tumor weight was measured at experimental endpoint.
Clonogenic assays revealed that in all bladder cell lines tested, an additive effect was observed in the combined treatment when compared to either treatment alone. Our data indicates that this effect is due to arrest in both G1 and G2 phases of cell cycle when treatments are combined. Furthermore, our data show that this arrest is primarily regulated by changes in levels of cyclin D1, p27 and p21 following treatments. In vivo, a significant decrease in tumor weight was observed in the combined treatment compared to either treatment alone or control.
Altering cell cycle by inhibiting the mTOR signaling pathway in combination with radiation have favorable outcomes and is a promising therapeutic modality for bladder cancer.
PMCID: PMC3684614  PMID: 23799002
15.  Correction: A Novel Mechanism of PPAR Gamma Induction via EGFR Signalling Constitutes Rational for Combination Therapy in Bladder Cancer 
PLoS ONE  2013;8(5):10.1371/annotation/50295123-3bb7-4916-812c-fa4ea5f09130.
PMCID: PMC3650997
16.  Human resource assessment of academic urology across Canada: What are the future job prospects? 
Our objective was to capture an overview of anticipated staffing needs at Canadian urology academic centres over the next 5 years to help guide and counsel urology residents in their respective programs.
A 30-question survey was sent by email to all chairmen of academic urology divisions/departments during fall 2012. The first part of the survey solicited basic demographic information regarding number of residents, number of fellows and fellowships, and number of attending staff and affiliated hospitals. The second part of the survey included detailed questions on the number and sub-specialty of urologists needed at each respective institution, as well as the appropriate year of recruitment.
The response rate was 100%. There are 13 urology training programs across Canada located in 6 out of the 10 provinces. Robotic surgery is available at 9 out of the 13 centres. A total of 68 urologists need to be recruited by academic institutions throughout Canada within the next 5 years. The greatest need is for general urologists, with a total of 13 required. This is followed by 12 urologic oncologists needed, 11 female urology, 7 reconstructive urologists, 6 pediatric urologists, 6 endourologists, 5 transplant surgeons, 4 infertility/andrology, and 4 experts in advanced laparoscopy/robotics. There was no need for any urologic trauma surgeons in any academic institution surveyed.
A total of 68 urologists need to be recruited into academic urology across Canada within the next 5 years. This crucial information can be used to help guide urology residents in choosing the most appropriate fellowship, in addition to providing them with an overview of future job prospects at academic institutions throughout the country.
PMCID: PMC3699074  PMID: 23826042
17.  Risk of cancer-specific mortality following recurrence after radical nephroureterectomy 
Annals of surgical oncology  2012;19(13):4337-4344.
To describe the natural history and identify predictors of cancer-specific survival in patients who experience disease recurrence after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).
Of 2,494 UTUC patients treated with RNU without neoadjuvant chemotherapy, 597 patients experienced disease recurrence. 148 patients (25%) received adjuvant chemotherapy before disease recurrence. Multivariable Cox regression model addressed time to cancer-specific mortality after disease recurrence.
The median time from RNU to disease recurrence was 12 months (IQR 5–22). 491 of 597 (82%) patients died from UTUC and 8 patients (1.3%) died from other causes. The median time from disease recurrence to death of UTUC was 10 months. Actuarial cancer-specific survival estimate at 12 months after disease recurrence was 35%. On multivariable analysis that adjusted for the effects of standard clinico-pathologic characteristics, higher tumor stages (HR pT3 vs. pT0-T1: 1.66, p=0.001; HR pT4 vs. pT0-T1: 1.90, p=0.002), absence of lymph node dissection (HR 1.28, p=0.041), ureteral tumor location (HR 1.44, p<0.0005) and a shorter interval from surgery to disease recurrence (p<0.0005) were significantly associated with cancer-specific mortality. The adjusted 6, 12 and 24 months post-recurrence cancer-specific mortality was 73%, 60% and 57%, respectively.
Approximately 80% of patients who experience disease recurrence after RNU die within two years post-recurrence. Patients with non-organ-confined stage, absence of lymph node dissection, ureteral tumor location and/or shorter time to disease recurrence died of their tumor faster than their counterparts. These factors should be considered in patient counseling and risk-stratification for salvage treatment decision-making.
PMCID: PMC3576920  PMID: 22805867
urothelial carcinoma; upper urinary tract; recurrence; survival; prognosis
18.  A Novel Mechanism of PPAR Gamma Induction via EGFR Signalling Constitutes Rational for Combination Therapy in Bladder Cancer 
PLoS ONE  2013;8(2):e55997.
Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy.
Principal Findings
As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner.
These results suggest that PPARγ agonist DIM-C can be an excellent alternative to bladder tumors resistant to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.
PMCID: PMC3568080  PMID: 23409107
19.  Extensive renal infarction following percutaneous biopsy of a small renal mass: A case report 
Percutaneous renal biopsy has become increasingly used particularly in patients undergoing active surveillance for small renal masses. We present a patient, who was recently diagnosed with laryngeal squamous cell carcinoma, with significant complication following biopsy of a solid renal mass. The patient was planned for nephron-sparing surgery that was converted to radical nephrectomy due to extensive renal infarction secondary to significant subcapsular hemorrhage inflicted by the biopsy.
PMCID: PMC3650821  PMID: 23671500
21.  Regional differences in practice patterns and associated outcomes for upper tract urothelial carcinoma in Canada 
We delineated Canadian regional differences in practice patterns in the management of upper tract urothelial carcinoma (UTUC) after nephroureterectomy and relate these to patient outcomes.
A database was created with 1029 patients undergoing radical nephroureterectomy for UTUC between 1994 and 2009 at 10 Canadian centres. Demographic, clinical and pathological variables were collected from chart review. Practice pattern variables were defined as: open versus laparoscopic nephroureterectomy, management strategy for the distal ureter, performance of lymphadenectomy and administration of chemotherapy and/or radiation therapy. The outcome measures were overall (OS), disease-specific (DSS) and recurrence-free survival (RFS). The centres were divided into three regions (West, Central, East). Cox proportional multivariable linear regression analysis was used to determine the association between regional differences in practice patterns and clinical outcomes.
There was a significant difference in practice patterns between regions within Canada for: time from diagnosis to surgery (p = 0.001), type of surgery (open vs. laparoscopic, p < 0.01) and method of management of the distal ureter (p = 0.001). As well, there were significant differences in survival between regions across Canada: 5-year OS (West 70%, Central 81% and East 62%, p < 0.0001) and DSS (West=79%, Central=85%, East=75%, p = 0.007) were significantly different, but there was no difference in RFS (West 47%, Central 48%, East 46%, p = 0.88). Multivariable linear regression analysis demonstrated that the differences in survival were independent of region OS (p = 0.78), DSS (p = 0.30) or RFS (p = 0.43).
There is significant disparity in practice patterns between regions within Canada, but these do not appear to have an effect on survival. We believe that the variability in practice is a reflection of the lack of standardized treatments for UTUC and underlines the need for multi-institutional studies in this disease.
PMCID: PMC3526631  PMID: 23282664
22.  Natural history of pT3-4 or node positive bladder cancer treated with radical cystectomy and no neoadjuvant chemotherapy in a contemporary North-American multi-institutional cohort 
The present study documents the natural history and outcomes of high-risk bladder cancer after radical cystectomy (RC) in patients who did not receive neoadjuvant chemotherapy during a contemporary time period.
We analyzed 1180 patients from 1993 to 2008 with >pT3N0 or pT0-4N+ bladder cancer who underwent RC ± standard (sLND) or extended (eLND) lymph node dissection from 8 Canadian centres.
Of the 1180 patients, 55% (n = 643) underwent sLND, 34% (n = 402) underwent ePLND and 11% did not undergo a formal LND. Of the total number of patients, 321 (27%) received adjuvant chemotherapy. The median follow-up was 2.1 years (range: 0.6 to 12.9). Overall 30-day mortality was 3.2%. Clinical and pathological stages T3-4 were present in 6.1% and 86.7% of the patients, respectively; this demonstrates a dramatic understaging. Overall survival (OS) at 2 and 5 years was 60% and 43%, respectively. Patients who received adjuvant chemotherapy had a 2- and 5-year disease-specific survival (DSS) of 72% and 57% versus 64% and 51% for those who did not (log-rank p = 0.0039). The 2- and 5-year OS for high-risk node-negative disease was 67% and 52%, respectively, whereas for node-positive patients, the OS was 52% and 32%, respectively (p < 0.001). The OS, DSS and RFS for patients with pN0 were significantly improved compared to those who did not undergo a LND (log-rank p = 0.0035, 0.0241 and 0.0383, respectively).
This series suggests that bladder cancer outcomes in advanced disease have improved in the modern era. The need for improved staging investigations, use of neoadjuvant chemotherapy and performance of complete LND is emphasized.
PMCID: PMC3529724  PMID: 23283097
23.  Outcomes of pT0N0 at radical cystectomy: The Canadian Bladder Cancer Network experience 
Radical cystectomy is the standard treatment for muscle invasive bladder cancer. We assessed clinical outcomes in patients found to have no evidence of disease (i.e., pT0N0) following radical cystectomy.
We collected and pooled a database of 2287 patients who underwent radical cystectomy between 1993 and 2008 in eight centres across Canada. Of this number, 135 patients were found to have pT0N0 bladder cancer at the time of cystectomy. Survival data and prognostic variables were analyzed using Kaplan-Meier method and Cox proportional hazard regression analysis.
Median patient age was 66 years with a mean follow-up of 42 months. Clinical stage distribution was Tis 8.9%, Ta 1.5%, T1 20.7%, T2 45.2%, T3 5.2%, and T4 5.2%. The five-year recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were 83%, 96%, and 88%, respectively. The 10-year RFS, DSS and OS were 66%, 92%, and 70%, respectively. On Cox proportional regression analysis, no variables were associated with disease recurrence and only patient age was associated with overall survival.
Patients with pT0N0 pathology after cystectomy have excellent outcomes with high five- and 10-year RFS, DSS and OS. However, there is still a risk of tumour recurrence in this patient population and thus postoperative surveillance is still required.
PMCID: PMC3377737  PMID: 22709882
25.  The Role of Radical Cystectomy in Patients with Clinical T4b Bladder Cancer 
Urologic oncology  2010;29(2):157-161.
Patients with clinical T4b bladder cancer (extension to pelvic wall and/or adjacent organs other than prostate, vagina or uterus) are commonly considered unresectable. We hypothesized that select patients might achieve durable benefit from multiagent chemotherapy and extirpative surgery.
We identified patients with clinical T4bN0 bladder cancer from our IRB-approved database of patients undergoing radical cystectomy (n =1194). Relevant demographic, clinical and pathologic data were compiled. Overall (OS), disease-specific (DSS) and recurrence-free survival (RFS) were analyzed by Kaplan-Meier estimation. Cox proportional hazards regression modeling was used to evaluate the influence of several potential prognostic factors.
Twenty-three patients (16 male) with a median age of 65 years met study criteria. Chemotherapy was administered pre-operatively to 19 (83%) and post-operatively to 8 (35%) patients. Eight patients died of disease and one of other causes. The 1-, 2- and 5-year DSS was 91% (95% C.I. 70–98%), 66% (95% C.I. 42–83%) and 60% (95% C.I. 34–78%), respectively. Eight of 17 patients with pT2-4 tumors succumbed to disease compared to none of 6 who were ≤ pT1 (p=0.04). Other predictors of decreased DSS included positive surgical margins (HR=5.34, 95% C.I. 1.25–22.83) and presence of pathologic nodal metastasis (HR=29.33, 95% C.I. 3.13–275.19). Variant histology was more common in this cohort than in the overall cystectomy database (43% vs. 11%).
Long-term survival can be achieved in a proportion of patients with cT4b bladder cancer undergoing chemotherapy and extirpative surgery. Careful selection of patients and meticulous surgical technique to avoid positive margins are critical.
PMCID: PMC2950900  PMID: 20456984
bladder cancer; cystectomy; chemotherapy

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