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The therapeutic benefit of pelvic lymph node dissection (PLND) at radical prostatectomy is still under debate. The overall effect of standard or extended node dissection on prostate cancer survival outcomes are complicated by variation in patient populations and study outcomes in most retrospective reviews. We report our findings of therapeutic effect of PLND for Ontario patients after radical prostatectomy.
The information sources for the study included electronic clinical data such as the Ontario Cancer Registry (OCR) and supplemented through an extensive chart review conducted by trained abstractors according to a standardized protocol. We used a retrospective case-cohort approach to assess the effect of lymph node removal on prostate cancer-specific mortality. A parent study population included a random sample of 1703 patients treated for cure in Ontario between 1990 and 1998, as well as 591 cases selected based on death from their prostate cancer within 10 years of diagnosis. From this group 313 patients meeting inclusion criteria for this study were identified. A Cox-proportional hazards model was used to determine the association between number of lymph nodes removed and risk of prostate cancer death, considering baseline disease characteristics, treatment and age as potential confounders. In a secondary analysis, the results were stratified based on nodal status.
The crude hazard ratio (HR) showed a marginally statistically significant reduced risk of prostate cancer mortality as the number of LN removed via PLND increased (HR: 0.92, 95% CI: 0.84 – 1.01). None of the variables considered as confounders caused a change in the LN hazard ratio of greater than 10% and therefore were not included in the adjusted model. Stratification based on pathological nodal status did not significantly (>10%) change the HR.
These results seem to confirm a trend to therapeutic benefit of greater node removal with reduced prostate cancer mortality although the study was slightly underpowered. In this case-control study design of mostly low-to-intermediate risk patients in Ontario, the possible therapeutic benefit of PLND was found to be independent of pathological nodal status.
Transrectal ultrasound (TRUS)-guided prostate biopsy is widely used to confirm the diagnosis of prostate cancer. The technique has been associated with significant morbidity in a small proportion of patients.
We conducted a population-based study of 75,190 men who underwent a TRUS-guided biopsy in Ontario, Canada, between 1996 and 2005. We used hospital and cancer registry administrative databases to estimate the rates of hospital admission and mortality due to urologic complications associated with the procedure.
Of the 75,190 men who underwent a TRUS biopsy, 33,508 (44.6%) were diagnosed with prostate cancer and 41,682 (55.4%) did not have prostate cancer. The hospital admission rate for urologic complications within 30 days of the procedure for men without cancer was 1.9% (781/41,482). The 30-day hospital admission rate rose from 1.0% in 1996 to 4.1% in 2005 (p-value for trend <0.0001). The majority of hospital admissions (72%) were for infection-related reasons. The probability of being admitted to hospital within 30 days of having the procedure rose four-fold between 1996 and 2005 (odds ratio = 3.7; 95% C.I.: 2.0 – 7.0, p < 0.0001). The overall 30-day mortality rate was 0.09%, but did not change over the study period.
The hospital admission rates for complications following a TRUS-guided prostate biopsy have risen dramatically over the last 10 years, primarily due to an increasing rate of infection-related complications.
We have extensively examined and shown the predictive value of the human kallikrein-2 (hK2) protein and its gene, KLK2, to be an important predictor for prostate cancer at the time of screening biopsy. Extensive sequencing analysis has identified two single nucleotide polymorphism (SNPs) (rs2664155-G/A and rs198977-C/T) to be highly associated with prostate cancer (Nam et al, Clin Can Res, 2006). We examined whether these SNPs and hk2 serum levels could predict cancer at the time of repeat biopsy among patients with an initial negative biopsy.
We genotyped 941 men who underwent a repeat prostate biopsy using an extended biopsy pattern after an initial negative biopsy for the two KLK2 SNPs. We also measured hk2 serum levels prior to initial prostate biopsy. All other baseline risk factors and tumour markers were measured, including age, ethnicity, family history of prostate cancer, PSA, prostate volume and DRE. Logistic regression analyses were conducted to determine the significance of KLK2 SNPs and hK2 levels for predicting cancer at repeat biopsy.
Of the 941 patients, 180 (19.1%) were found to have cancer. The baseline model of age, ethnicity, PSA, prostate volume and past histology were all important predictors for cancer. Mean serum hK2 levels were also significantly higher among cases (246.0 ng/mL) compared to controls (227.9 ng/mL, p < 0.02). Among the two SNP variants, rs198977 was positively associated with cancer at repeat biopsy (OR variant T allele = 1.5, 95% CI: 1.1–2.1, p = 0.01). The KLK2 rs198977 genotypes were positively associated with hK2 levels (p = 0.02). The addition of hK2 levels and KLK2 SNP to the baseline predictive model increased the area under the curve from a baseline model of 0.69 to 0.71 (p = 0.01). Hk2 and KLK2 genotype was more important for prostate cancer detection than PSA. When combined, the odds ratio for prostate cancer for patients with high hK2 levels and the variant T-allele of rs198977 was 3.77 (95% CI: 1.94 – 7.32, p < 0.0001), compared to patients with low hK2 levels and the C-allele.
The KLK2 variant SNP, rs198977, was positively associated with hK2 levels and predicts prostate cancer at the time of repeat prostate biopsy. These findings may provide important information for the clinical management of patients being considered for repeat prostate biopsy after an initial negative biopsy.
Postoperative prostate-specific antigen (PSA) doubling time (PSADT) is an important predictor of prostate cancer-specific mortality in patients treated with radical prostatectomy. Whether PSA kinetics at very low PSA values reflects that of higher PSA values is unknown. In this retrospective cohort study, we test the hypothesis that, within the same patient, PSA kinetics differs across different PSA levels.
From the CaPSURE prostate cancer registry, we included all patients treated with radical prostatectomy from 1995 to 2008, that had at least 4 non-zero postoperative PSA measurements. Patients who had any neoadjuvant or adjuvant therapy were excluded. We compared the PSADT across range of PSA, in subject having at least 2 PSA measurements both below (early PSADT) and above (late PSADT) 0.2 ng/mL. A paired analysis was conducted using exact McNemar and kappa tests. The risk of short (aggressive) late PSADT was also assessed using conditional logistic regression models and c-statistics were used to assess the additional predictive value of early PSADT. The base model included age and cancer risk as covariables.
The study population included 3098 patients, with a mean age of 63 (SD 6) years. The vast majority of cancer risk at diagnosis was intermediate or lower: 12 (4.8%) patients had a Gleason score of 8 or more, 7 (2.8%) patients had a clinical stage T3 or more and 19 (7.6%) patients had a PSA greater than 20. Overall, the mean PSADT was of 17.7 months (SD 1010.1). Late PSADT significantly differed from early PSADT (McNemar statistic p < 0.01). Early PSADT overestimates the aggressiveness of late PSADT (i.e., late PSADT is longer) in 77 (25%) patients. Early PSADT underestimates the aggressiveness of late PSADT (i.e. late PSADT is shorter) in 32 (10%) patients. The findings of the comparison analyses were robust to sensitivity analyses where the PSADT comparison cut-point varied from 3 months to 24 months, and where the threshold value for defining early versus late PSA varied from 0.1 to 0.4 ng/mL. At multivariate analysis, a short early PSADT doubled the risk of a short late PSADT (OR 1.87, 95% CI: 1.01–3.45, p = 0.046) but adds very little accuracy to the model (no change the c-statistic of 0.62).
After radical prostatectomy, PSA kinetics at very low PSA values significantly differs from the kinetics at higher PSA values as commonly evaluated after PSA recurrence. Early PSA kinetics may be more likely to overestimate the aggressiveness of later PSA kinetics. PSA kinetics in the very low PSA range should be interpreted with caution, and may not be the ideal biomarker to help select patients for adjuvant therapy.
Salvage treatment of prostate cancer recurrence following external bean radiation therapy (EBRT) is morbid, as such many minimally invasive approaches have been trialled. The primary problem with comparing salvage techniques following EBRT is the lack of long term data. We reviewed the long term salvage cryotherapy to the prostate gland in a single institution, single surgeon series.
A retrospective analysis was performed on all patients undergoing salvage cryotherapy for locally recurrent prostate cancer after EBRT by a single surgeon at our institution from 1995–2004. Preoperative, perioperative and postoperative data was reviewed and recorded. Follow-up mortality data, PSA results, bone scan results and any details of hormone therapy were recorded for this study.
There were 187 patients included in the current study, from which 176 patients had records available for follow-up, giving a follow-up rate of 94%. Mean follow up was 7.46 years (1–14 years). Fifty-two patients were followed for greater than 10 years. Prostate cancer recurrence, when it occurred, was at an average of 2.3 years following cryotherapy. Average time to hormone therapy in these patients was 2.8 years. Results are summarized in Table 1.
|5 years n = 126||8 years n = 88||10 years n = 52|
|Disease free survival*||38%||27%||15%|
|Disease free survival (pre-salvage PSA <4 ng/mL*)||79%||39%||43%|
|Disease free survival (pre-salvage PSA >4 ng/mL*)||27%||24%||11%|
|Disease specific survival||94%||95%||96%|
This study represents the longest and largest single centre salvage cryotherapy series in the literature. Disease free survival rates of 43% were achieved at 10 years in patients with pre-salvage treatment PSA <4ng/mL whilst it was only 11% in those with a PSA >4ng/mL. 10 year overall and disease specific survival was high regardless of disease recurrence. We believe that with appropriate patient selection cure can be attained with salvage cryotherapy, however it is important to note that 10-year survival was high regardless of disease status. We believe that salvage cryotherapy not only for curing selected patients but also has a role in delaying the introduction of hormone therapy and reducing tumour burden.
Accumulating evidence demonstrates that androgen deprivation therapy (ADT) is associated with osteoporosis and fragility fractures of the spine, hip, and wrist. One study has suggested ADT use may also be associated with non-fragility fractures in older men. Whether other clinical risk factors independently increase the risk of fractures is not certain. We sought to confirm whether ADT increases the risk of non-fragility fractures and fractures leading to hospitalization. We also explored other risk factors for fractures in men on ADT.
Using linked administrative databases in Ontario, Canada, men age 66 or older with prostate cancer on continuous ADT for at least six months or who underwent bilateral orchiectomy (n = 19,079) were matched with men with prostate cancer who had never received ADT. Matching variables included age, prior cancer treatment, year of diagnosis, comorbidities, medications, prior fractures, and socioeconomic variables. Primary outcomes were development of a typical fragility fracture, any fracture, and fractures requiring hospitalization. Independent predictors of fracture outcomes were assessed using Cox proportional hazards models.
Over a mean 6.47 y of follow-up, ADT use was associated with an increased risk of both fragility fracture (hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.53, 1.78) and any fracture (HR 1.46, 95% CI 1.39, 1.54). ADT users had a higher frequency of fractures requiring hospitalization as well as hip, other femur, wrist, upper arm, spine, lower leg, and pelvic fractures (all p < 0.05) but not fractures of the hand, skull, ribs, or feet. Independent predictors (p < 0.05) of fragility fracture included increasing age (HR 1.79 for 75–84 year olds and HR 3.23 for 85+ compared to 65–74 year olds), prior use of bone-thinning medications (HR 1.25), chronic kidney disease (HR 1.33), prior dementia (HR 2.14), prior fragility fracture (HR 3.43), a prior diagnosis or treatment for osteoporosis (HR 1.39), and regular access to a primary care physician (HR 0.82). The same variables were independent predictors of any fracture.
Continuous ADT use for at least 6 months in older men is associated with an increased risk of a variety of fractures and fractures requiring hospitalization. Increasing age and prior osteoporotic fracture are common and important clinical factors that may warrant greater consideration of anti-osteoporotic therapies in these men.
Previous 1-year trial results (CS21) comparing leuprolide, a gonadotropin-releasing hormone (GnRH) agonist, to degarelix, a new generation GnRH antagonist, demonstrated several differences which appear to favor degarelix such as: time to suppression of testosterone, luteinizing hormone and prostate-specific antigen (PSA); level of FSH and alkaline phosphatase suppression, musculoskeletal adverse events (AEs), time to PSA recurrence and PSA progression-free survival (PFS). Here we report long-term effects on PSA control and musculoskeletal AEs in patients on continuous degarelix treatment compared to patients switched from leuprolide to degarelix.
There were 610 patients with histologically confirmed prostate cancer (all stages) were randomized to leuprolide 7.5 mg/month, degarelix 240 mg/80 mg (starting dose/monthly maintenance dose) or degarelix 240/160 mg (CS21). After 1 year, patients were offered entry into an extension trial (CS21A). 135 leuprolide patients were re-randomized to degarelix 240/80 mg or 240/160 mg treatment. 251 degarelix patients continued on their respective dose. PSA PFS was defined as time to first PSA recurrence (2 consecutive increases in PSA of ≥50% compared with nadir and ≥5 ng/mL on 2 consecutive measurements at least 2 weeks apart) or death.
During the first year (CS21), risk of PSA recurrence or death was significantly less in patients receiving degarelix 240/80 mg versus leuprolide (p = 0.05; log-rank). After up to 3 years total exposure, PSA PFS hazard rate for continuous degarelix went from 0.11 during the first year (CS21) to 0.14 thereafter (CS21A) (p = 0.45) while a significant decrease from 0.20 to 0.09 was observed in leuprolide patients switched to degarelix (p = 0.01). Musculoskeletal AEs were 17% during the first year (CS21) and 16% thereafter (CS21A) for continuous degarelix while a decrease from 26 to 18% in was observed for leuprolide patients switched to degarelix.
Extension trial data of patients initially treated for 1 year with leuprolide who then switched to degarelix showed an improved control of PSA and fewer musculoskeletal AEs. The differences may reflect the different mode of action of degarelix compared to leuprolide.
The introduction of medical therapy for symptomatic benign prostatic hyperplasia (BPH) during the last 2 decades may have shifted the indications, patient characteristics and outcomes in men undergoing TURP over the last 2 decades (1988 to 2008).
All patients who underwent TURP for symptomatic BPH in a geographically defined area at our Institution in 1998 (before general introduction of medical therapy for BPH), 1998 (when medical therapy was becoming an important therapy for BPH), and 2008 (medical therapy was the primary initial therapy for BPH) were reviewed. We assessed total number of TURPs, indications for surgery, patient age, health status, weight of resected tissue, and pre- and postoperative complications.
There was a 60% decrease in TURPs from 1988 (n = 157) to 1998 with a moderate increase in number in 2008. Failure of medical therapy was not an indication in 1988 but was at least one of the indications for TURP in 36% and 87% in 1998 and 2008 respectively. No significant differences were found in age. There was a significant rise in patients presenting with chronic urinary retention at the time of their TURP (15% in 1988, 20% in 1998 and 39% in 2008), but fewer patients presented with hydronephrosis in 2008 (7.1%) compared to 1998 (12.5%) but this was still much higher than in 1988 (1.3%). Postoperative days in hospital decreased over the decades (from 4.1 days in 1988 to 2.7 in 1998 and then to 2.1 days in 2008); however, the number of patients discharged with a catheter (failure to void) increased over 2 decades (from 3.2% to 12.5% to 28.6% respectively).
The dramatic decrease in the number of TURPs performed for symptomatic BPH at our Institution since the advent of medical therapy has now leveled off. However, the proportion of TURP patients presenting with urinary retention and the number being discharged with a catheter after a failed trial of voiding has increased. This would suggest that although the average age and medical co-morbidities of our TURP patients has not dramatically changed, patients currently presenting for TURP appear to have experienced more pre-TURP progression and poorer immediate outcomes over the decades from 1988 to 2008. Could this be a direct result of increasing reliance on medical therapy?
The primary patient source of dissatisfaction following inflatable penile prostheses (IPP) surgery is penile length compromise, which can be due to broad underlying patholphysiologies including post-prostate cancer treatment (surgery, radiation or brachytherapy) and diabetes. Traditional teaching dictates that the implanting surgeon choose shorter sizing when measuring corporal length at the time of IPP placement if there is a discrepancy in the measuring of the two sides of the corpora or, as more commonly occurs, sizing that equals the symmetrical corporal lengths measured. In fact, some prosthetic surgeons advocate using shorter than measured corporal lengths. Recently, a novel New Length Measurement Technique (NLMT) has been developed and we present patient outcome data and an evaluation of current sizing trends. Methods: Retrospective primary IPP chart reviews of 57 IPP patients comparing a multi-surgeon practice (n = 10, the multisurgeon group (MSG)) versus 57 IPP patients from a single surgeon (SS) prior to using the NLMT technique versus 283 patients with more that one year follow up done by the same single surgeon [GH] (SS NLMT). American Medical Systems (AMS) and Coloplast data on cylinder sizes used nationwide over the past several years was also analyzed.
The average cylinder size plus rear tip extender length utilized by the MS group was 19.05 cm, compared to SS 20.11 cm and SS NLMT 23.37 cm. A single distal erosion in the MS group (semi rigid rod) was noted, with none in the SS or NLMT surgery groups. AMS data suggests an increase in percentage sales of 21 and 24 cm IPP cylinders with a resultant decrease in percentage sales of 12 and 15 cm IPP cylinder over the past 2 years. Coloplast cylinder distribution is similar (Fig. 1).
There appears to be a paradigm shift in utilizing longer cylinders when analyzing changes in cylinder size sales for IPP implantation. No increases for distal erosion in the SS experience with NLMT is evident when compared to traditional sizing outcomes.
The relationship between endothelial dysfunction and erectile dysfunction (ED) is irrefutable. Given the data from Inman et al (Mayo Clin Proc 2009), and previously Thompson et al (JAMA 2005), the importance of screening for ED cannot be underestimated, especially in the third through fifth decades, as ED is associated with a marked increase in the risk of future cardiac events. However, physician-practice analyses to date have not indicated that ED is routinely screened for as part of patient care, especially in these younger patients.
Annually from 2005 through 2008, a total of 528, 380, 381, and 355 Canadian men, respectively, were surveyed by third-party national data-gathering organizations (2005–2007 Maritz Health and 2008 IPSOS, Canada) for analysis of patient encounters with primary care, urologist or other physicians regarding ED evaluation and treatment.
Physician-initiated evaluation for erectile dysfunction is poor. For all years (n = 1644 men), greater than 85% of all ED evaluation (Question “Who initiated the discussion of ED”) was initiated by the patient. ED screening was rare as part of periodic health evaluations (routine check-up). Of PDE-5 inhibitor prescriptions, 77–89% (dependent year/agent) were prescribed by primary care physicians. It is interesting to note that by 2008, “first” information on ED via the internet rose to 15%; other sources of information including pharmacists, other media etc, seem to play a minor role in the Canadian healthcare environment.
A key aspect of men’s health includes identifying and modifying cardiovascular risk factors prior to onset of morbidity. As gatekeepers for the majority of ED health initiatives, new strategies for urologists to inform and educate Canadian primary care physicians and patients are of great importance. Delivery of quality sexual healthcare and endothelial health/screening is an unmet patient need in many cases. Contemporary data demonstrate that the CUA must continue to demonstrate leadership on local and national levels for educating not only the patient but also our non-specialist colleagues, in order to improve male health care.
Orgasm associated incontinence, that is the inadvertent leakage of urine at orgasm, has received little attention in the literature but confers significant quality-of-life and health-system impact post-radical prostatectomy (RP). Recent reports estimate occurrence of up to 20–48%; in Mulhall’s report of 475 RP patients (pts), 96 reported orgasm associated incontinence (J Urol 177(6): 2223-6) independent of age, nerve sparing or surgical margin status, seminal vesicle or lymph node involvement, preoperative erectile function, nocturnal erections, libido level or daytime continence. In this study, we prospectively evaluate and report the first series determining the impact of the Advance Male Sling (American Medical Systems, MN) for men with pharmacologically treatment-resistant mild-to-moderate incontinence and climacturia.
Prospective data on a specific population of 15 pts with incontinence and climacturia was collected. The primary endpoint was complete resolution of climacturia, with concurrent evaluation of post-sling urinary control. All pts were at least 1.5 years post-RP (2 pts with adjuvant radiotherapy) prior to incontinence surgery, and underwent placement of the AdVance male sling after evaluation consisting of history, physical examination, determination of pad-per-day (PPD) incontinence, cystoscopy, and video urodynamics/pad weight tests as indicated for 3 or more ppd leakage. The pts underwent outpatient re-evaluation at 2, 6 and 12 weeks post-surgery and ongoing treatment efficacy was assessed q6 months with regards to pad-free status, flow rate, and post-void residuals in addition to yes/no of any urinary leak during sexual activity.
Median pt follow-up is 50 weeks (range 12–71 weeks). Age was 67 +/− 6 yrs. Preoperative pad use ranged from 1– 4 pads/day. All men had complete resolution of climacturia. 13/15 (87%) pts were completely dry with no pad use, and 2/15 pts reported persistent 1 PPD incontinence; these were men initially identified with 2+ PPD leakage and concurrent detrusor overactivity on urodynamics (one post adjuvant radiation), and were counselled regarding potential limitations of the sling approach. No sling infections or revision surgery were reported, and post-procedure transient urinary retention did not require secondary surgical intervention.
The Advance Male Sling represents a safe and efficacious treatment for mild to moderate incontinence following RP and prospective data specific to this population supports resolution of concurrent climacturia at 1-year follow-up. Multicentre confirmation of this clinically important outcome, and determination of patient factors predictive of potential non-resolution for climacturia following surgery are required.
Surgical placement of a 3-piece inflatable penile prosthesis (IPP) and Advance Male Sling (MS) (American Medical Systems, MN) is an important treatment option for men with concurrent treatment-resistant erectile dysfunction (ED) and mild-to-moderate incontinence, especially following treatments for prostate cancer. Medium to long-term experience of a simultaneous approach is reported.
Prospective data for 22 patients treated by simultaneous placement of the Advance MS and a 3-piece IPP was collected. Patients were followed for postoperative care at 1, 2 and 6 weeks post-surgery (daily inflation of the IPP at 2 weeks), and returned to full, unrestricted activities including intercourse at 6 weeks. Ongoing treatment efficacy is assessed q6 months; interval questionnaire data was supplemented by phone interviews.
Patient follow-up of 22 months (mdn) is reported. Operating time was 92 min (range 49–102). IIEF-5 scores increased by 18.6 +/−0.9, with 18/22 patients using the IPP for intercourse; 16/18 (89%) patients describe themselves as “satisfied” or “very satisfied” with the penile implant and 2/18 (11%) are “unsatisfied” (both due to penile length loss). Preoperative pad use ranged from 1– 5 pads/day. Two out of 22 patients (10%) reported persistent incontinence requiring daily pad use; these were men with 3–5 ppd leakage prior to surgery and were counselled regarding potential limitations of the sling approach in this group. These are men outside of standard inclusion criteria for MS. 19 men (86%) report complete continence and 1 reports the “occasional” use of a protective pad (0–1 pad/week). Four of 22 patients (18%) experienced urinary retention postoperatively lasting from 3–10 days, which resolved without secondary surgical intervention. Prosthetic infections or revision surgery did not occur.
Simultaneous 3-piece IPP and Advance male sling placement is a safe, effective treatment combination for men suffering from post-prostatectomy urinary incontinence and erectile dysfunction. This approach may also confer a potential health-system economic benefit without compromise of patient outcomes.
The male AdVance sling is a relatively new option for management of post-prostatectomy incontinence. We present our retrospective cohort of patients and their early outcomes.
Between January 2007 and November 2008, 31 male patients suffering from urinary incontinence after prostate surgery were treated with a transobturator synthetic sling (AdVance sling). Preoperative evaluation included history, urodynamics, and cystoscopy. Postoperatively, patients completed a self-administered mailed questionnaire describing lower urinary tract symptoms, the impact of urinary incontinence and overall satisfaction (UDI-6, IIQ-7 and IPPS-QOL).
Mean age of the patients was 69 years (57–81). Etiology of the incontinence was post-radical prostatectomy (28), post-TURP (1) and post high intensity focused ultrasound (HIFU) + TURP (1). Seven patients had previous radiation therapy. Mean time from prostate surgery to sling insertion was 5 years (range 1.2–12.3). Preoperative cystoscopy revealed bladder neck contraction in 11 patients. Preoperative urodynamics demonstrated a mean capacity of 461 mL (268–800), and valsalva leak point pressure (VLPP) of 110 cm H2O (57–247); 4/30 had reduced compliance and 9/30 had detrusor overactivity. Mean postoperative follow-up time was 21.75 months (range 12–32). Preoperatively the mean number of pads used per day was 2.3, and postoperatively this number decreased to 1.1 pads per day (p < 0.001). Postoperatively, 10/31 men (32%) did not wear pads any more, 7/31(23%) used 1 pad, 10/31(32%) 2 pads, and 4/31(13%) used more than 2 pads per day. After the implantation of the sling 3 patients required additional procedures – AUS was implanted in 1 patient and 2 patients underwent sling tightening. No patients have had problems with tape infection or fistulae. Mean postop IPPS QOL score was 2.4 (0–6): 53% were very satisfied, 13% mixed, and 33% were dissatisfied. In the 7 patients who had prior radiation the mean decrease in pads worn per day (2.14 to 1.57) was not significant (p = 0.382), whereas the decrease in pads per day in the 24 without prior radiation was significant (2.67 to 1.21).
Initial results from the AdVance sling indicate that it provides a good and reliable alternative to the artificial urinary sphincter for management of incontinence post prostate surgery. Prior radiation is an adverse factor. However, the majority of patients are satisfied with their continence outcome and quality of life after the AdVance sling.
Bladder cancer often recurs after surgical intervention and there is debate with regards to the optimal follow-up strategies. We sought to review our data on the recurrence patterns following radical cystectomy with the aim to establish appropriate surveillance protocols for patients with localized and locally advanced bladder cancer.
We collected and pooled a database of 2,287 patients who have undergone radical cystectomy for carcinoma of the bladder between 1993 and 2008 in 8 different academic centres across Canada. Of these, 1,890 patients had complete recurrence information and form the basis on this report.
Total of 825 patients (43.6%) developed recurrence. According to location, 218 were distant (48.6%) with the remaining divided into: 113 pelvic (25.2%), 65 retroperitoneal (14.5%) and 53 to multiple sites (11.8%) such as pelvic and retroperitoneal or pelvic and distant. Most common distant sites were lungs (42%), bone (35.5%) and liver (27%). Median time to recurrence for entire population was 10.1 months (range 0 to 192.4) with 90% and 97% of all recurrences happening by 2 and 5 years post-cystectomy, respectively. When stratified according to stage, tumours with positive nodes (pTxN+) were more likely to recur than extravesical node-negative tumours (≥pT3N0) and organ-confined node-negative tumours (≤pT2N0) (57% vs. 40.1% vs. 21.5% respectively, p < 0.0001). Similarly, pTxN+ tumours had a shorter median time to recurrence (9.1 months, range 0 to 71.6 months) compared to ≥pT3N0 tumours (9.5 months, range 0 to 69.5 months) and ≤pT2N0 tumours (13.7 months, range 0 to 192.4 months, p < 0.0001).
Differences in recurrence patterns between the different subgroups after radical cystectomy suggest the need for varying follow-up protocols for patients in each. Chest radiographies are recommended once yearly for ≤pT2N0 tumours; every 6 months for the first 2 years then annually thereafter for ≥pT3N0 tumours; and every 3 months for the first year, then every 6 months thereafter for pTxN+ tumours. Triphasic CT scans of abdomen and pelvis are recommended on a yearly basis for ≤pT2N0 tumours; every 6 months for the first 2 years then annually thereafter for ≥pT3N0 tumours; and at 3 and 6 months postoperatively then every 6 months thereafter for 2 years then annually for pTxN+ tumours.
The objective of this study was to compare clinical and pathologic outcomes of radical cystectomy for muscle-invasive bladder cancer in relation to prior history of superficial transitional cell carcinoma.
Retrospective data collected from 2287 patients managed by radical cystectomy for transitional cell carcinoma of the bladder from the Canadian Bladder Cancer Network were analyzed. Patients with clinical stage T2 or more were included and divided into two groups: (1) patients with prior history of superficial transitional cell carcinoma of the bladder, and (2) patients with clinical muscle-invasive cancer de novo. Variables analyzed included patient age, gender, pathologic stage, adjuvant chemotherapy and survival.
Both groups were nearly equal in the mean age and gender distribution, with mean age of 67.2 and 66.7 years, and 79.7% and 79.5% of patients being men in groups 1 and 2, respectively. The presence of preoperative hydronephrosis was 20.8% and 32.6% (p = 0.0007) for groups 1 and 2, respectively. The incidence of higher pathological stage (T3 or T4) was 36.3% and 58% (p <0.0001), positive lymph nodes was 20.1% and 28.8% (p = 0.002) and lymphovascular invasion was 31.7% and 46.2% (p = 0.0001) for groups 1 and 2, respectively. The incidence of adjuvant chemotherapeutic treatment was 15.5% and 23.3% (p = 0.002) for groups 1 and 2, respectively. The overall survival (OS) and the disease specific survival (DSS) at 5 years was 62% and 70% for group 1 and 51% and 60% for group 2 respectively. At 10 years, 46% and 66% for group 1 and 35% and 49% for group 2, respectively (p [log-rank]= 0.0002 and 0.0001, respectively). In multivariate analysis, studying factors affecting OS, DSS and tumour recurrence, the presence of previous superficial bladder tumour was found to be associated with a significant reduced risk of mortality and tumour recurrence (Hazard ratio of 0.7 for all risks).
Our retrospective study suggests that patients with superficial transitional cell carcinoma of the bladder that progress to muscle-invasion and require radical cystectomy appear to have better pathologic and clinical outcome than patients presenting with clinical muscle-invasive disease de novo.
Post chemotherapy retroperitoneal lymph node dissection (pcRPLND) for residual retroperitoneal disease is the standard of care for non-seminomatous germ cell tumours. The management of men whose retroperitoneal disease completely responds to chemotherapy is more controversial and some centres recommend RPLND to remove microscopic disease that may progress to late relapse. We have retrospectively evaluated our experience with the management of patients who presented with retroperitoneal (RP) metastases and who underwent initial chemotherapy to determine if pcRPLND was indicated in those who achieved a complete response (CR) in the RP.
The charts of the 305 consecutive patients from the Princess Margaret Hospital Testis Tumor Clinic who presented to the clinic with RP adenopathy and who received initial chemotherapy were reviewed.
Of these 305 men, 131(42.9%) achieved a CR in the RP as assessed by imaging (defined as residual adenopathy <1 cm in maximal axial dimension) and were observed. Nine (9 or 6.8%) later relapsed and all were salvaged (6 RPLND only, 2 salvage chemotherapy+RPLND, 1 RPLND+chemotherapy). Full bilateral pcRPLND with postganglionic sympathetic nerve preservation where possible was done in 144 men with residual RP disease. Thirty did not achieve an initial response of whom 50% died of disease.
Our experience in unique in that we report the outcomes of all men who present with RP adenopathy managed by initial chemotherapy and not just those who either undergo RPLND or are managed expectantly. In our total experience, 42.9% achieved a CR in the RP. Without further therapy (pcRPLND), only 6.8% of these patients relapsed and all were salvaged. Our experience strongly supports continuing surveillance as opposed to surgery in this population.
The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the targeted therapy era is unknown and is being addressed in randomized trials. Experience with preoperative treatment is increasing and the indication and timing of CN is not clear. We report our preliminary experience with sorafenib before CN.
Patients (pts) with mRCC and who were deemed suitable for CN at diagnosis were eligible. Patients had a renal biopsy prior to treatment. Oral sorafenib (400 mg PO BID), with dose reduction as needed, was administered for 12 wks preoperatively and restarted post-CN until disease progression, or stopped at investigator discretion. The primary aim was to determine the relationship between pathological response data and time to progression. Feasibility, tolerability and response to preoperative sorafenib are presented.
Thirteen men with biopsy-proven clear cell RCC (mean age 55yr, range 40–70) have been enrolled to date. Mean age was 55 years (range 40–70). No unusual toxicities were observed on sorafenib. Pre-op radiological response data were available for 12/13 patients. Ten patients (77%) had stable disease by RECIST after preoperative sorafenib, 6 of whom had a decrease in disease burden (mean decrease 14%, range 5–25%). One patient had partial response (PR) and 1 had progressive disease. The mean response in primary tumour was an 11.6% decrease (range +36% to −54%). Of the 10 patients who underwent CN, there was one postoperative death, unrelated to treatment protocol. Increased perinephric fibrosis has been observed at surgery, but no other notable findings or postoperative complications were seen. Three patients did not have surgery: 1 due to marked early progression, 1 because of possible drug-related cardiotoxicity which led to surgical delay, and 1 is awaiting surgery. On pathology review, no morphologic differences were noted in viable tumour before and after sorafenib; 1 patient with clinical PR had near complete pathological response. Five patients continued sorafenib postoperatively due to ongoing benefit.
Preoperative sorafenib in mRCC was well-tolerated, resulted in over 50% of patients having tumour size reductions in both primary and metastatic sites and did not appear to impact feasibility or tolerability to subsequent CN. Complete pathological and biomarker data are awaited.
Partial nephrectomy is the gold standard for management of most small renal masses. Cryoablation is a viable alternative with a favourable morbidity profile and good efficacy. We compared intermediate oncologic and functional outcomes following laparoscopic partial nephrectomy (LPN) and renal cryoablation (RC) from a multicentre experience.
We present a multicentre retrospective review of LPN and RC experience between 09/1998 and 10/2009. LPN was performed via a transperitoneal approach, while RC was performed via percutaneous or transperitoneal laparoscopic approach. Persistent mass enhancement or interval tumour growth was considered a treatment failure following RC. Residual enhancing tumour was evidence of treatment failure following LPN.
Data on 376 (234 LPN, 142 RC) patients were included for study. No significant differences with respect to gender, ethnicity and BMI were noted. Mean follow-up was significantly longer in RC than LPN (36 vs. 20 months, p < 0.001). Mean age was 56.2 (LPN) and 66.8 (RC) years (p < 0.001); 18% LPN and 28% RC had diabetes mellitus (p = 0.03). Mean tumour size was 2.5 (LPN) and 2.5 (RC) cm (p = 0.34). Preoperatively, 16.4% LPN and 38% RC had eGFR <60 mL/min/1.73 m2 (p < 0.001). On univariate analysis, development of de novo eGFR<60 mL/min/1.73 m2 occurred in 9.7% LPN and 15.6% RC patients (p = 0.125). Tumour persistence/recurrence was noted in 1.7% LPN and 7.8% RC (p = 0.042). Disease-free survival (DFS) was 98.6% in LPN and 92.9% in RC (p = 0.007). On univariate analysis, DFS was associated with younger age (p = 0.015), non-African American race (p = 0.04) and LPN (p = 0.007). Overall survival was 99% and 97% in LPN and RC cohorts (p = 0.71), respectively.
In this multicentre study of LPN and RC with intermediate follow-up, RC had higher primary treatment failure rates than LPN. DFS was significantly higher with LPN. RC did not provide superior renal preservation when compared to LPN. While further follow-up is needed, caution should be exercised in offering cryoablation as a primary treatment modality to younger, healthy patients.
There remains disagreement as to whether the location of upper urinary tract cancer affects prognosis. We examined the significance of ureteral and renal pelvic upper tract urothelial carcinoma (UC) in a large multi-institutional study.
We collected and pooled a database of 700 patients with upper tract UC who underwent radical nephroureterectomy. Univariate and multivariate models examined the effect of tumour location on recurrence-free (RFS) and cancer-specific survival (CSS) rates. Collected variables included age, gender, race, presence of lymphovascular invasion, concomitant carcinoma in situ, pathological stage/nodal status, lymph node dissection and type of surgery (open vs. laparoscopic).
The median follow-up for patients alive was 42 months (IQR: 20–76). With regards to location, 34% of tumours were ureteral, 59% pelvic and 7% were multifocal. Tumour location was significantly associated with lymphovascular invasion (p = 0.035), pathological stage (p = 0.014), race (p < 0.001) and type of surgery (p = 0.038). It was, however, not associated with age (p = 0.206), gender (p = 0.858), grade (p = 0.511), lymph node dissection (p = 0.259), number of nodes resected (p = 0.084), nodal status (p = 0.422), concomitant CIS (p = 0.296), or follow-up duration (p = 0.508). On multivariate analyses adjusting for age, gender, race, surgical type, stage, grade, nodal status, lymphovascular invasion and concomitant CIS, ureteral tumour location when associated with multifocal disease remained an independent predictor of both RFS (p = 0.004) and CSS (HR p = 0.035).
Contrary to recent data, our results show that ureteral tumour location in association with multifocal disease is an independent prognostic factor for both RFS and CSS.
Well designed systematic reviews (SR) and meta-analyses (MA) rank high in the hierarchy of levels of evidence, but their usefulness to influence clinical practice depends on their quality. We sought to analyze the quality of published SR and MA in pediatric urology.
A search for all SR and MA published between Jan 2000-Nov 2009 in 5 top pediatric urology journals was conducted using Pubmed (MEDLINE) and EMBASE with the following limits: “Humans”, “Meta-Analysis”, Review”, “Historical Article”, English”, and “All Child: 0–18 years.” Two reviewers independently selected articles for full-text review. Scientific methodological quality was assessed independently by 2 raters, using CEBM (5-item) and AMSTAR (11-item) tools. Disagreement was resolved by consensus. The overall scores for both tools were compared using Pearson correlation coefficient.
Titles and abstracts were initially reviewed (n = 267) of which 220 were excluded since they were narrative reviews, historical articles, surveys and case reports. Full text evaluation (n = 47) resulted in further exclusion (n = 32, inappropriate age group – adults), leaving 15 for the final analysis. Seven of these were published in 2009 (47% vs. 10% -previous years, p < 0.01) and 12 (80%) were exclusively pediatric. Eleven (73%) reviews reported use of keywords only to search for articles and no more than 4 (27%) reported contact with experts. Only 1 (7%) review had a full search strategy described, while 4 (27%) reported use of grey literature and 3 (20%) inclusion of articles in a language other than English. In 8 (53%), selection of studies was performed by 2 reviewers, independently in 5 (33%) and blindly in none. Five (33%) reviews described some form of quality assessment of the included studies, 8 reported (53%) agreement between raters and 6 (40%) mentioned that discrepancy was resolved by consensus. Only 5 (33%) reviews reported assessment of publication bias by funnel plot while 8 (53%) checked for heterogeneity among studies and 10 (66%) presented some form of pooled statistics. Using AMSTAR criteria, 7 (47%) reviews were considered as having less than fair methodological quality, 5 (33%) fair to good quality and 3 (20%) good quality. When the CEBM tool was used, 6 (40%) reviews were rated as less than fair quality, 4 (27%) fair to good and 5 (33%) good. Comparison of the overall score between the 2 measurement tools revealed high agreement (r2 = 0.76).
Despite the recent increase in the number of SR and MA published in Pediatric Urology journals, almost half of these reviews lack good scientific quality, raising concerns about their role to influence clinical practice. Efforts should be made to improve the methodological quality of SRs and MAs in the pediatric urology literature.
Conventional Laparoscopic Fowler-Stephens Orchidopexy (CLO) is conducted when spermatic vessels’ length limits adequate testicular mobilization. Despite its widespread acceptance as a 1 or 2-stage procedure, atrophy rates can be as high as 30%. In such cases division of cremasteric vessels during advancement medial to the inferior epigastric vessels is likely the culprit. Gubernaculum-sparing laparoscopic orchidopexy (GSLO) – which involves anatomical delivery of the testis through the internal inguinal ring (IIR) – has been proposed as an alternative to CLO maximizing collateral blood supply and potentially reducing atrophy rates. Herein, we test this hypothesis by comparing the 2 techniques.
A retrospective chart review of 135 pts who underwent surgical management for non-palpable testis (NPT) between 2001 and 2008 was performed. We excluded 16 pts due to missing data resulting in a study sample of 119. The following variables were captured: age at surgery, location of intra-abdominal testis (IAT) testis – high or low, type of surgery (CLO or GSLO, 1 or 2 stages), and atrophy rates. A high IAT was diagnosed when > 2 cm from IIR. Atrophy was defined as the presence of a nubbin or impalpable testis on follow-up, confirmed by Doppler ultrasound. Comparative analyses between CLO and GSLO, and between 1 vs. 2-stage procedures were performed using the Chi-square test.
Out of 119 pts 14 had bilateral NPT for a total of 133 gonads. Mean age at surgery and follow-up were 25±12 and 26±20 months respectively. 22 testes were palpable under general anesthesia and thus managed by inguinal orchidopexy. Laparoscopy was carried-out for the remaining 111 children, showing: vanishing IAT in 16 (14%), vanishing inguinal in 30 (27%) and IAT in 65 (59%; 21-low and 44-high). A 1-stage procedure was performed in 23 (35%) cases and 2-stage in 42 (65%). CLO was undertaken in 23 patients (35%) and GSLO in 42 (65%), based on surgeon preference. The overall atrophy rate was 7.7% (5/65). Five of 23 testes atrophied after CLO vs. none of 42 following GSLO (22% vs. 0%, p = 0.01). Of 23 CLO, 9 were done in 2 stages and 14 in a single stage. One atrophy (high testis) was documented after 2-stage CLO vs. 4 (2-high, 2-low testes) atrophies after 1-stage CLO [11% (1/9) vs. 29% (4/14), p = 0.34]. No case of 1-stage GSLO (0/7) developed atrophy. At last follow-up evaluation all but one viable testis were found in a normal scrotal position.
GSLO is a feasible alternative to CLO. Our findings suggest that the added vascular supply to the testis (cremasteric vessels) rather than the type of procedure (1 vs. 2-stage) significantly influences testicular atrophy rates. Further prospective comparative studies with CLO are needed to establish whether GSLO truly improves IAT salvage rates.
Dysfunctional elimination syndrome is associated with an inability to effectively empty the bladder and may present with UTI, incontinence, intestinal constipation or other voiding symptoms. Biofeedback has emerged as one potentially effective and non-invasive treatment. We sought to analyze if biofeedback is an effective method to treat these children less than 18 years of age.
A literature search was conducted in MedLine, EMBASE, CINAHL, Cochrane Database, AUA, CUA and AAP abstracts. Copies of all relevant articles were retrieved for quality assessment and data abstraction by two independent reviewers. Primary outcomes were UTIs and daytime incontinence. Primary outcomes of recurrent UTI and incontinence were analysed using pooled estimates. Also, I2 was calculated to determine heterogeneity between studies using an adapted formula of Higgins and Pearson’s chi-square statistic.
Twenty-seven studies were included (1 RCT and 26 case-series). The pooled estimate showed 83% (95% CI: 79%–86%) and 81% (95% CI: 76%–85%) improvement in UTI and daytime incontinence (Fig. 1) (Fig. 2). I2 statistic showed “Low” (3%) and “High” (76%) heterogeneity across studies results for UTI and daytime incontinence. The only included RCT favored biofeedback over standard therapy (RR 1.4, 95% CI: 0.98–2.00) but this was not statistically significant. There was also improvement in constipation (18%–100%), frequency (67%–100%), urgency (71%–88%) and VUR (21%–100%). PVR improvement ranged from 26 mL-99 mL and Qmax improvement was from 3.1 mL/s - 4.7 mL/s.
Based on this review, biofeedback is an effective, non-invasive method of treating dysfunctional elimination syndrome, and approximately 80% of children benefited from this treatment. However, most reports were of low level of evidence and studies of more solid design such as RCT should be conducted.
Creation of a continent catheterizable channel (CCC) has dramatically changed the management of patients undergoing lower urinary tract reconstruction. As many interventions are carried out during childhood it is particularly important to look at long-term problems due to the inherent life expectancy of this population. Herein we present outcomes and complications on a single-centre series followed up to 15 years.
Medical records of all children who underwent CCC (Mitrofanoff and Monti) between 1992 and 2007, regardless of indication for surgery, were retrospectively reviewed. Data were systematically collected for the following variables: Age, underlying diagnosis, associated procedures, stoma site, tissue used for creating of the conduit (appendix or reconfigured bowel), time to complications (stenosis, prolapse, incontinence) and need for revision.
At a mean age of 7.5 years (6m-22yrs.), 71 girls and 98 boys were evaluated, with a subsequent follow-up of 5.8 years (8m-15y). Underling diagnosis included neurogenic bladder (36%), bladder exstrophy (25%), epispadias (7%) and rhabdomyosarcoma in (5%). Concurrent procedures (bladder augmentation, 35%; bladder neck plasty, 22%; bladder neck closure, 8%) were done in 71% of cases. The overall complication rate was 39% (stenosis/stricture, 25%; incontinence, 10%; prolapse, 4%). Even though an initial peak was followed by a stable complication-free period, on long-term follow delayed problems were detected (Fig. 1). Most CCC (96%) were functional at last follow-up including 8% in which the channel could not be salvaged and had to be recreated. On a time-to-event analysis no statistically significant differences in complications rates comparing use of appendix vs. Monti CCC, underlying diagnosis, age or stoma position were noted.
Complications after CCC appear to decrease over time but late problems are detected on long-term evaluation. In our experience no factors predicted likelihood of complication. At long-term follow-up good outcomes were encountered despite need for revision.
UDS are routinely performed for evaluation and decision making for spina bifida patients (pts). Little data exists to whether UDS findings actually alter clinical impression and change management plans for spina bifida pts beyond what is obtainable by ultrasound. We sought to evaluate the impact of UDS on the change of management.
A retrospective analysis of spina bifida pts with neurogenic bladder who underwent UDS in 2006 and 2007 was performed. Pts who did UDS as routine preoperative assessment were excluded. Demographic data and ultrasound findings were recorded. Change in management was defined as alteration of frequency of CIC, dose or frequency of anticholinergics or scheduling surgery.
The study included 133 pts, mean age 9.5 yrs (range 2 months -18 yrs). A change in management based on UDS was identified in 57 pts (42%). Among those 25 (18%) had CIC schedule revision, 53 (39%) had anticholinergic dose adjustment and 12 (9%) had surgery scheduled (7 augmentation cystoplasty, 2 mitrofanoff, 1 sling, 1 botox injection, 1 bladder neck closure). There was no significant difference in age and sex in patients whose management was altered or not. Upper tract status by ultrasound was a significant predictor of change in management. Of pts with normal sonographic upper tracts, 27% had change of management based on UDS findings versus 95% who had change of management when the upper tracts were abnormal (p < 0.05).
Around half of the children with neurogenic bladder will have change of management on follow-up. Although UDS remains to be routinely performed, those with abnormal sonographic upper tracts are more likely to have change of management. UDS may be unnecessary in evaluation of pts with normal upper tracts.
To compare the results of a low trans-scrotal mid-raphe orchidopexy in patients with palpable undescended testes (UDT), to a high-scrotal incision (Bianchi) and to the conventional inguinal approach.
We used a retrospective cohort study design. All orchidopexies performed at our institution between January 2003 and September 2009 with a minimum of 3-month follow-up were included. All palpable UDT that could be brought down manually into the upper third of the scrotum under general anaesthesia, were then reviewed (group 1: high-scrotal incision, group 2: low-scrotal incision) and compared to the inguinal two-incision technique (group 3). We excluded cases of inguinal orchidopexy requiring Prentiss manoeuvre, children who had undergone previous inguinal surgery, and patients with concomitant surgeries. We comprehensively reviewed the charts and focused on the following outcomes: operative time, success as defined by mid or lower scrotal position of the testicle, and complications at 6–12 weeks and 1-year after surgery.
A total of 286 orchidopexies were performed in 214 patients with palpable UDT. In group 1, a high-scrotal incision was performed in 44 patients for 60 UDT (success 59/60, 98%) with one recurrence. A modification to the technique was adopted and since November 2005, patients in group 2 had a trans-scrotal orchidopexy through a single low-scrotal incision on the median raphe. It was performed in 81 patients for 125 UDT. All testes except 1 (99%) were located in a good position within the scrotum. In group 3, a standard inguinal two-incision orchidopexy was performed in 89 patients for 101 UDT (success 100%). The mean operative time for unilateral UDT was significantly shorter for the low trans-scrotal orchidopexy (mean 28 min, SD 10, vs. mean 37 min, SD 12; p < 0.001) than for the inguinal orchidopexy but equivalent to a high scrotal incision (27+/−10 min; p = 0.59). One patient approached by high-scrotal incision required conversion to a traditional inguinal approach. All patent processes vaginalis were ligated, regardless of their size. In all 160 children followed at 1 year, no long term atrophy or secondary reascent were observed. Postoperative complications included transient postoperative scrotal hematoma in a single patient who had a high-scrotal incision and 2 wound infections in the inguinal approach group.
Low trans-scrotal mid-raphe orchidopexy appears to be an excellent alternative to the high-scrotal incision or the standard inguinal orchidopexy for low palpable UDT especially for bilateral cases. Scrotal orchidopexy is simple, safe, and effective in selected cases.
Shock wave lithotripsy (SWL) is considered the first-line treatment for the majority of patients with renal and ureteric calculi, with success rates for contemporary series varying from 60–90%. Although success is dependent on patient and stone-related factors there are few reliable algorithms predictive of SWL success. We conducted a retrospective analysis of patient and stone-related factors to determine their influence on the success of SWL and develop a comprehensive nomogram to predict SWL outcomes.
Data from patients treated at the St. Michael’s Hospital Lithotripsy Unit from May 2004 to June 2009 were reviewed. Analysis was restricted to those patients with a pre-treatment non-contrast CT scan conducted at our centre demonstrating a solitary renal or ureteric calculus ≤ 20 mm in maximal diameter. Successful treatment of renal stones was defined as those patients who were stone free or had asymptomatic, clinically insignificant residual fragments <4 mm in diameter three months after a single SWL treatment. Successful treatment of ureteric stones was defined as stone free 2-week post-SWL. Demographic, stone, patient, treatment and follow-up data were collected from a prospective database and review of CT and KUB imaging by two independent urologists and one radiologist. Data was analyzed with logistic regression, Chi square analysis and ANOVA where appropriate.
There were 422 patients (69.7% male) with a mean age of 51.4 years (SD 12.9) and mean BMI 27.0 kg/m2 (SD 4.9) analyzed. Mean stone size was 78.9 mm2 (SD 77.3) for ureteral stones and 66.1 mm2 (SD 63.2) for renal stones, with 95 (43.6%) of the renal stones located in the lower pole. The single treatment success rates for ureteral and renal stones were 62.3% and 68.8%, respectively. On univariate analysis, predictors of SWL success, regardless of stone location, were age (p = 0.01), BMI (p = 0.01), stone size (p < 0.001), skin-to-stone distance (SSD; p < 0.001), and CT attenuation (CTHU, p = 0.003). On multivariate analysis, age > 60 (OR=0.60, p = 0.011), stone size >45 mm2 (OR=0.35, p < 0.001), and SSD >110 mm (OR=.49, p < 0.001) remained significant predictors of outcome.
We have identified patient and stone parameters that can reliably predict SWL outcomes for both ureteral and renal stones. This data can be used by clinicians to facilitate optimal treatment-based decisions and provide patients with more accurate single-treatment success rates for SWL that are tailored to patient-specific situations.
The holmium:YAG laser fragments stones by photothermal mechanism. Increased pulse energy produces larger ablation craters, implying faster lithotripsy. However, increased pulse energy produces more retropulsion, implying slower lithotripsy. We studied optimal power settings for holmium:YAG lithotripsy.
Stone phantoms of uniform shape and mass were ablated in water with 500 J total energy (n = 10 per cohort). Six power settings were tested: 0.2 J at 10 Hz, 0.2 J at 50 Hz, 0.5 J at 10 Hz, 0.5 J at 40 Hz, 1.0 J at 10 Hz, 2.0 J at 10 Hz. Two conditions were tested: no stabilization device vs. a PercSys Accordion stabilization device placed behind the stone. After lithotripsy, fragments were dried and passed through sequential geological sieves. To quantify fragment size distribution, we reported the % fragments >1 mm of the top 10%ile largest fragments per cohort. Total fragmentation (TF) was defined as initial mass minus the dominant remaining mass. In the “no device” cohorts, retropulsion was measured. ANOVA, Kruskal-Wallis, Mann-Whitney and t-tests were used for statistics.
|0.2 J 10 Hz||0.2 J 40 Hz||0.5J 10 Hz||0.5J 40 Hz||1.0 J||2.0 J||p-value|
|TF no device (g)||0.01 ± 0.00||0.02 ± 0.01||0.04 ± 0.01||0.02 ± 0.01||0.05 ± 0.01||0.05 ± 0.01||<0.0001|
|% >1 mm, no device||0||0||22||5||4||1||0.06|
|Retropulsion (mm), no device||26 ± 6||22 ± 5||58 ± 15||63 ± 9||98 ± 15||152 ± 38||<0.0001|
|TF + device (g)||0.01 ± 0.01||0.03 ± 0.01||0.05 ± 0.01||0.05 ± 0.01||0.09 ± 0.03||0.14 ± 0.03||<0.0001|
|% >1 mm, + device||0||0||10||15||37||36||<0.0001|
Comparing no stabilization vs. stabilization for each power cohort, TF increases with stabilization devices, except for 0.2 J 10 Hz and 0.5 J 10 Hz cohorts, p < 0.01; fragment size increased with stabilization for 1.0 J and 2.0 J cohorts, p < 0.0001 (Table 1).
When retropulsion is constrained by a stabilization device, increasing pulse energies produce more lithotripsy but also larger fragments. With no stabilization device, increasing pulse energies produce more retropulsion with less efficient lithotripsy. At low pulse energy, fragments are small but lithotripsy is less efficient. The optimal power settings appear to be low pulse energy (0.2 – 0.5 J) at high frequency (40 Hz). The findings are consistent with photothermal effects at low pulse energy and increased photomechanical effects at higher pulse energies.
Ureteroscopy is associated with significant radiation exposure to patients, urologists and operating room personnel. The most effective method of reducing occupational radiation exposure is to shorten the fluoroscopy time. The aim of the present study was to assess prospectively the impact of recording fluoroscopy time in the operative report on the use of fluoroscopy during ureteroscopy.
Sixty-four ureteroscopies for consecutive patients presenting for stone disease at the McGill University Health Centre were included in the study. These patients were divided into 2 groups based on the attending endourologist. Group I did not have fluoroscopy times recorded, whereas in group II, the attending endourologist recorded intra-operative fluoroscopy times in the operative report. Seven procedures were excluded (3 ureteroscopies did not have fluoroscopy time documented by either the radiologist or the urologist and 4 ureteroscopies were for staghorn calculi). Therefore, there were 24 ureteroscopies in group I and 33 ureteroscopies in group II. Patient and stone characteristics were obtained from hospital and office charts and both groups were compared using the Mann–Whitney–Wilcoxon test. Kruskal-Willis tests were used to compare fluoroscopy times between the 2 groups after correcting for stone size, location, and sidedness.
There were no significant differences between group I and group II in terms of average age (55 vs. 53 years, p > 0.4), percentage female (42% vs. 24%, p > 0.1), and percentage renal stones (58% vs. 63%, p > 0.6). Similarly, there were no significant differences between the two groups in terms of mean stone size (11 vs. 9 mm, p > 0.1), and mean stone volume (1039 vs. 648 mm3, p > 0.2). Intra-operative average fluoroscopy time was significantly higher in group I when compared with group II (277 vs.169 seconds, p < 0.01). This statistical significance remained even when both groups were corrected for stone size (p < 0.02), stone location (p < 0.02), and sidedness (p < 0.03).
Documentation of fluoroscopy times in ureteroscopy reports makes the urologist cognizant of radiation exposure and may lead to significant reductions in the use of fluoroscopy during ureteroscopy. Although these differences may be due to different intra-operative practices of urologists, surgeon behaviour remains the most significant modifiable factor in fluoroscopy use during ureteroscopy.
A wide range of therapeutic options are available for the management of urolithiasis. We sought to describe the practice variability of CUA members and factors which predict these patterns for common stone scenarios.
Three hundred and eight English and 52 French-speaking CUA members were asked to complete online surveys in their respective languages. Demographic information on practice location, endourology fellowship training, Extracorporeal Shock Wave Lithotripsy (ESWL) access, “academic” vs. “community” practice, and whether at a hospital with regionalized surgical services, was collected. Respondents were asked to indicate actual as well as ideal treatment for scenarios of renal, proximal and distal ureteric calculi.
|Stone size (mm)||Open ureterolithotomy||PCNL||Ureteroscopy and intra-corporeal lithotripsy / stone retrieval||ESWL||Cystoscopy and ureteric stent insertion under general anesthetic||Cystoscopy and ureteric stent insertion under local anesthetic||Analgesia, medical expulsive therapy, and close follow-up||Analgesia and close follow-up||Total|
|4||Actual||0 (0)||0 (0)||7 (5.1)||2 (1.4)||0 (0)||0 (0)||105 (76.6)||23 (16.8)||137|
|Ideal||0 (0)||0 (0)||34 (17.4)||3 (1.5)||1 (0.5)||1 (0.5)||108 (55.4)||48 (24.6)||195|
|8||Actual||0 (0)||0 (0)||77 (57.5)||10 (7.5)||3 (2.2)||3 (2.2)||37 (27.6)||4 (3.0)||134|
|Ideal||0 (0)||0 (0)||108 (54.3)||29 (14.6)||3 (1.5)||4 (2.0)||44 (22.1)||11 (5.5)||199|
|14||Actual||0 (0)||1 (0.8)||106 (80.3)||8 (6.1)||5 (3.8)||7 (5.3)||4 (3.0)||1 (0.8)||132|
|Ideal||0 (0)||1 (0.5)||120 (65.9)||36 (19.8)||10 (5.5)||6 (3.3)||8 (4.4)||1 (0.5)||182|
There were 131 urologists who responded (36 % response rate), all of whom treat urolithiasis. Of these: 38% practiced in Ontario, 17% in Quebec, 12% in BC and 12% in Alberta; 17% had endourology fellowship training; 76% had access to ESWL; 42% were at an academic institution and 66% at institutions with regionalized surgical services. Actual and ideal treatment modalities selected for symptomatic, distal and proximal ureteric stones (4, 8, 14 mm) were consistent with published guidelines. There were discrepancies between the use of ureteroscopy and ESWL in actual versus ideal scenarios (Table 1). Actual and ideal practices were congruent for proximal ureteric stones and asymptomatic renal calculi. In multivariable analysis, respondents were less likely to perform ureteroscopy on proximal 4 and 8 mm stones if they were at a hospital with regionalized surgical services (OR: 0.097; 95% CI: 0.01–0.76, p = 0.03 and OR: 0.330; 95% CI: 0.13–0.83, p = 0.02). Academic respondents were more likely to choose ESWL for proximal stones (OR: 4.12; 95% CI: 1.70–9.98, p = 0.002 for 8mm and OR: 3.87; 95% CI: 1.59–9.44, p = 0.003 for 14 mm). Endourology training was the only predictor for use of PCNL (OR 4.02; 95%CI: 1.1–14.8, p = 0.04 for 22 mm renal pelvic stone and OR 3.395; 95% CI: 1.21–9.51, p = 0.02 for 15 mm lower calyceal stone).
There is a range of clinical variability in the management of urolithiasis in Canada, however, management approaches fall within published guidelines.
Percutaneous nephrolithotomy (PCNL) is the gold standard for management of large renal stones. Traditionally, patients are admitted postoperatively with a large-bore nephrostomy tube, which is removed after a normal nephrostogram on postoperative day two. Although tubeless PCNL has been described previously, there have been no reports of ambulatory tubeless PCNL. The aim of the present study was to assess the safety and feasibility of ambulatory tubeless PCNL. Here the initial 10 patients are presented.
The initial series of 10 patients undergoing ambulatory tubeless PCNL was included in the present study. Patient information including age, sex, fluoroscopy time, operating room time, stone size (using largest diameter), and Hounsfield Units (HU) were collected prospectively and analyzed retrospectively. Furthermore, number of needle punctures, number of tracts, and stone free status were ascertained. Amount of narcotic administered in the recovery room (mg morphine equivalents), amount of time spent in recovery room (minutes), amount of narcotics used at home, and complications were recorded and documented. Criteria for same day discharges were: single tract, stone free status, adequate pain control, and satisfactory postoperative chest X ray and CBC. All patients had antegrade double J stents placed intra-operatively. Male patients were discharged home with Foley catheter. Follow-up office visit was done on postoperatively 2 days for trial of void and removal of the flank dressing. Double J stents were removed a week later cystoscopically.
Out of the 10 patients undergoing ambulatory PCNL, 2 had established nephrostomy tracts. The rest of the 8 patients had nephrostomy tract established intra-operatively by the urologist. The median operating and fluoroscopy times were 83.5 and 4.45 minutes, respectively. The median stone diameter was 20 mm with a median of 800 HU. Patients spent a median of 240 minutes in the recovery room and received a median of 19.25 mg of morphine equivalents. There were no intra-operative complications and none of the patients required transfusions. There were two postoperative complications. The first was a deep vein thrombosis requiring anticoagulation. The second was re-admission for multi-resistant E. coli UTI requiring intravenous antibiotics.
In highly-selected patients, ambulatory tubeless PCNL is safe and feasible. More patients are needed to verify criteria for patients undergoing ambulatory approach.
Minimally invasive pyeloplasty has emerged as the standard of care for repair of UPJO. Herein, we review our international experience to evaluate outcomes of robotic and conventional laparoscopic pyeloplasty, comparing two large series with long-term scintigraphic and clinical follow-up.
Two university medical centre surgical teams have performed 107 robotic and 150 laparoscopic dismembered pyeloplasties, respectively, since 2002. An IRB-approved retrospective chart review was used to collect demographic, preoperative, operative, and postoperative data. Patients underwent a diuretic renal scan and symptom analysis pre- and post-surgery. Outcomes of laparoscopic and robotic pyeloplasty were analyzed using JMP 8.0 software.
Both groups had a mean follow-up greater then 2 years. The laparoscopic group treated more UPJO with suspected intrinsic etiology (p = 0.045) and had decreased operative time (p < 0.0001). The robotic group had decreased length of stay and a slightly improved postoperative scintigraphic radiographic resolution of obstruction (T ½ ≤ 20 minutes) and symptoms. There was a trend for an increased complication rate in laparoscopic pyeloplasty group (p = 0.08), including an increased urinary leak rate.
To our knowledge, this represents the largest series comparing laparoscopic and robotic pyeloplasty with a mean follow-up of greater then 2 years. Laparoscopic pyeloplasty is associated with shorter operative times. Robotic pyeloplasty appears to have shorter lengths of stay and improved rates of postoperative radiographic resolution and symptoms. There was a trend for decreased complications in the robotic group. Overall, both techniques appear to be effective treatment with good durable outcomes for the management of UPJO.
Encrustation of urologic devices can increase patient morbidity thereby limiting their clinical use. Alteration of stent materials and coatings has been attempted to limit encrustation. Encrustation is associated with organic salt deposits. Our objective was to develop a urologic device encrustation model that would mimic the in vivo process better than the ones that currently rely on either the actions of enzymes or bacteria. The ideal model would be: 1) rapid, 2) sterile, and 3) reproducible, using chemical solutions.
Four different stent types were tested using this model (Sof-Flex® [Cook Urological], Optima® [Bard Urological], Percuflex Plus® and Triumph®[both Boston Scientific Corp.], with each stent used in duplicate. Stent segments (1.5cm) were suspended in 500 mL artificial urine (AU) anchored to pipette tips positioned in the buoyant midsection of a pipette tip box. A modified version of Brooks and Keevil’s AU was used containing 7.5mM CaCl2. This media was replaced daily to better represent in vivo conditions and maintain sterility. Stent pieces were incubated at 37°C with 5.0 mM ammonium oxalate solution added constantly at a rate of 0.4 mL/min. After 7 days, the encrustation was photographed, physically removed and weighed. The mass of encrustation was compared amongst the different stent types. The results were the average of six independent experiments.
The slow, continuous addition of ammonium oxalate to AU promoted perpetual precipitation and deposition of crystals on all exposed surfaces. After 7 days, all device segments harboured visible surface encrustation. Encrustation was found to be the greatest on the Triumph® devices (8.20 ± 0.33mg/cm2) followed by Sof-Flex (6.00 ± 0.38), Percuflex Plus (5.45 ± 0.56) and Optima (4.38 ± 0.86). These differences were found to be statistically significant (p = 0.004).
This novel method can rapidly yield in vitro urologic device encrustation in the magnitude of milligrams/cm2. The protocol can be modified to hasten or slow the encrustation rate. One further benefit is the ability to test multiple stents simultaneously. This is the first method to produce non-urease-based encrustation in such a short period, using a setting of sterile artificial urine that is reproducible and closely mimics physiologic conditions. This model may be used in the future to advance stent design with the goal of improving clinical outcomes.
Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Infection of the urinary tract with uropathogenic E. coli (UPEC) is highly prevalent, and can incite significant morbidity and mortality. Although it is known that epigenetic mechanisms, such as DNA methylation, allow downregulation of host genes by bacteria, the pathogen factors responsible for this effect are generally unknown, and completely unknown for UPEC.
Persistent infection of urothelial cells with FimH[+] UPEC results in DNMT1 upregulation and CDKN2A hypermethylation which is associated with CDKN2A downregulation and increased cell proliferation. Infection with FimH[-] E.coli had no effect on DNMT1 expression, CDKN2A methylation or UC growth.
These results demonstrate that FimH adhesin plays an important role in the epigenetic reprogramming of host cell gene expression by E.coli, raising the possibility that CDKN2A methylation status may vary further with UTI recurrence. UTI and UTI recurrence can seriously compromise patients with dilated urinary tract pathologies, immunosupression, or other preexisting medical conditions. However the inability to predict which of these patients are at such risk for infection or recurrence often forces pre-emptive surgical correction of dilating uropathies and widespread indiscriminate antibiotic use. Identification of uropathogeic bacteria-induced gene methylation may constitute a biological marker for UTI recurrence, providing a valuable diagnostic tool for refining medical and surgical therapy for such patients, thereby curbing antibiotic use and reducing the incidence of prophylactic surgery.
Androgen receptor (AR) signaling is implicated in diverse stages of prostate cancer (PCa), from local to metastatic disease and even after endocrine therapy. Underlying mechanisms are not fully understood but aberrant AR signaling appears to contribute to progression. Earlier results from our lab and recent reports suggest a new form of AR activation via tyrosine (Y) phosphorylation in response to diverse growth-promoting factors. Our aim was to investigate whether the Fer kinase, which is overexpressed in PCa, controls AR activation in an environment containing interleukin-6 (IL-6) or androgens.
LNCaP cells were transfected with siRNA (fer and AR) or fer cDNA, wild-type and double mutant. Growth was monitored by MTT following exposure to IL-6 or synthetic androgen Methyltrienolone (R1881). PSA mRNA levels were measured by real-time PCR. Proteins (Fer, AR, STAT3) and their extent of Y-phosphorylation were analyzed by immunofluorescence, -precipitation & Western blotting. Pull-down assays were performed using the Fer-SH2 domain. The Fer kinase domain was used to phosphorylate recombinant AR in vitro.
In line with observations on IL6 mediating pSTAT3 crosstalk with AR signaling, we found that IL6 controls Fer/AR and Fer/pSTAT3 complexes together with their nuclear translocation and activation by Y-phosphorylation. Interestingly, R1881 stimulates the Y-phosphorylation and nuclear accumulation of both Fer and AR but not of STAT3. Both AR and pSTAT3 were found in Fer-SH2 pulldowns, inferring the coexistence of multi-molecular Fer complexes in PCa cells. In functional assays, down-regulation of fer and AR revealed a strict requirement of Fer and only partial of AR for IL-6 growth response, whereas the converse was observed for R1881. PSA levels were reduced when Fer was silenced and more so in the IL6 vs. R1881 context. Similarly the AR Y-phosphorylation was favored in presence of IL6. AR was also a direct Fer substrate.
Fer overexpression together with its ability to activate AR and control its nuclear translocation in response to IL-6 and low levels of androgens may explain PCa cell growth and PSA expression after endocrine therapy, thereby favoring progression of the disease.
siRNA specifically and efficiently degrade target mRNAs. The therapeutic potential of siRNAs to treat urological disease is limited by their short half lives and their short dwell time within the bladder. To increase the half-life of siRNAs within the bladder, we have loaded siRNA into nanoparticles and have complexed the nanoparticles with peptides that bind to urothelium.
We have incorporated fluorescein labeled siRNAs into anten-napedia (AP)-poly(lactide-co-glycolide) PLGA using spermadine as a complexing reagent to increase encapsulation efficiency. AP is a targeting peptide that was conjugated to PLGA to enhance intracellular delivery. Using siRNA-AP-PLGA nanoparticles, we tested release of siRNA into artificial urine, the uptake of fluorescence into T-24 bladder cancer cells using FACS cell sorting, and the downregulation of target mRNA and protein in T-24 cells and in human ureteral urothelium using real time PCR, ELISA, and western blots.
We have complexed vascular endothelial growth factor (VEGF) siRNA and survivin siRNA, survivin being an inhibitor of apoptosis, into PLGA nanoparticles and characterized their physical and chemical properties and their ability to downregulate target protein and mRNA. VEGF siRNA and survivin siRNA are released into artificial urine from fluorescein siRNA AP-PLGA nanoparticles for 10 days in amounts sufficient to downregulate target protein and mRNA. Similar concentrations of siRNAs complexed in lipids, are not detected after 24 hrs. Fluorescence is enhanced several fold in T-24 cells treated with fluorescein labeled siRNA–AP-PLGA for 3 and 4 days, indicating the uptake of siRNAs into cells. To confirm siRNA uptake, we measured downregulation of survivin levels. In T-24 cells treated with survivin siRNA AP-PLGA (1 mg/mL) for three days, survivin mRNA is decreased by 88% and there is a large decrease in survivin protein compared to cells treated with control AP-PLGA. In human urothelium treated with VEGF siRNA AP-PLGA for 5 days, VEGF levels were reduced 63%, (240 + 9 pg VEGF/mL) compared to urothelium treated with control AP-PLGA (655 + 39 pg VEGF/mL).
Encapsulation of VEGF and survivin siRNAs into AP-PLGA nanoparticles produced sustained siRNA release in sufficient amounts to downregulate target protein and mRNA in both cancer cells and normal urothelium.
Dietary restriction increases longevity may have potential benefits for injury-response and disease. Preclinical data has shown to improved outcomes from cervical spinal cord injury with candidate mechanisms including trkB, the receptor for brain-derived nerve growth factor (BDNF) which is a key cavernous nerve (CN) neuromodulator. The purpose of this study was to determine whether every-other-day-fasting (EODF), a form of intermittent caloric restriction, conferred an erectile recovery advantage following CN crush injury in the rat, focusing specifically on CN biology.
Forty-four 3-month old Sprague-Dawley male rats were separated into a control (sham, n = 8) group and cohorts consisting of 9 animals divided into crush-injury only (non-treated, no EODF), and treatment arms of EODF started 2 weeks prior to injury, EODF at day of injury, and EODF initiated 2 weeks post-CN injury. The change in intra-cavernous pressure (ICP) standardized to mean arterial pressure (MAP) at 5 months was measured, with this extended in-treatment phase chosen in order to aid in washing out of any short term fasting effects between groups. Tukey-Kramer test was used for post-hoc analysis and statistical significance was set at p < 0.5. The proximal corpora was cryosectioned and stained with primary antibodies against the catecholamine synthesis marker tyrosine hydroxylase, neuronal NO synthase (nNOS), and vesicular acetylcholine transporter (VaChT).
The mean maximal increase in ICP/MAP (with standard deviation) for control animals was 0.673 (.09) versus the crush-control cohort (no caloric modification) ICP/MAP change of 0.17 (0.06). Rats treated with EODF started two weeks prior to injury demonstrated significant (p < 0.05) improvement in erectile function with ICP/MAP ratio of 0.37 (0.07) Fasting started day of injury demonstrated less robust recovery, with 0.28 (.05) compared to the “pre-treated” group. The final group, starting EODF two weeks post injury demonstrated results statistically similar to no caloric restriction, with a ICP/MAP ratio of .168 (0.06). The two primary neurobiological endpoints in this study, retrograde axonal transport of fluorogold to the major pelvic ganglion and cavernous body determination of nNOS and VaChT were significantly reduced in crush injury, and 2 week post-injury EODF, compared to EODF initiated 2 weeks prior to/and day of injury.
This is the first study to demonstrate endogenous stress-response neuromodulation in a model of radical prostatectomy induced CN injury. Intermittent caloric restriction in the form of EODF confers a recovery advantage for CN function post injury as measured by ICP/MAP and intact parasympathic neurons.
For several years, fibroblast cells have been primarily used for tissue engineering but adipose-derived stem/stromal cells (ASCs) show promising potential due to their facility to obtain, their capacity to differentiate and their ability to secrete mediators. Our group previously reported on the production of a bioengineered vesical equivalent using dermal fibroblasts without exogenous matrix. The aim of this study was therefore to evaluate the possibility of engineering an autologous vesical equivalent with human ASCs in order to validate if our model can benefit from the attributes of the ASCs.
ASCs were obtained from lipoaspirated adipose tissue and fibroblasts were extracted from a dermal biopsy. These human cells were cultured with serum and ascorbic acid to stimulate the formation of extracellular matrix and obtain cell sheets. Cells were cultured with constant media motion (Gyrotwister™, Woodbridge, NJ) during three weeks and then three cell sheets of ASCs or fibroblasts were superimposed. After 4 days of maturation allowing cell sheet fusion, human urothelial cells were seeded on top of the construction and matured at the air/liquid interface. The vesical equivalents were characterized by histology, immunofluorescence as well as mechanical and suture resistance tests.
Complete vesical equivalents were obtained with ASCs or fibroblasts. The histology clearly showed that cell sheets forming the ASC vesical equivalents featured a strong cohesion between cell sheets and were 1.8-fold thicker than the fibroblast vesical equivalents. Immunolabelings of the mature constructions showed the presence of cytokeratin 8\18, a differentiation marker for urothelial cell; and collagen 1 and 3, which are the major components of the extracellular matrix. The ASC vesical equivalents were easy to manipulate resistant enough to suture, therefore allowing the 3D reconstruction of a bladder shaped tissue engineered substitute.
Human vesical equivalents were successfully produced using either dermal fibroblats or ASCs, without the use of exogenous scaffolding components. The ASC vesical equivalents could sustain suturing without tearing. Considering their accessibility, abundance and increased matrix production ACSs therefore represent a great cell source to further optimize our innovative model for vesical reconstruction.
We reviewed our data of laparoscopic donor nephrectomies with multiple renal arteries. We evaluated the donor and recipient outcomes on these donors.
All donor nephrectomies performed at our centre from 2004 to 2008 were reviewed retrospectively. Results were compared between laparoscopic donor nephrectomy kidneys with multiple arteries and those with a single vessel.
Out of 171 donor nephrectomies, 21 (12%) were performed for kidneys with multiple renal arteries. Of the 150 (88%) donor nephrectomies in the single vessel group all were performed laparoscopically. In the multiple artery group 9 (43%) underwent an open procedure while 12 (57%) underwent the procedure laparoscopically. The results were evaluated for laparoscopic donor nephrectomy kidneys with multiple and single renal artery. The warm ischemia time was longer in multiple artery group but was not statistically significant (4.25mins ± 0.87 vs. 4.12 mins ± 0.95). Regarding the transplant recipients the vascular anastomosis time was similar in both groups (30 mins ± 4.6 vs. 29.5 mins ±3.7). The operative blood loss in the transplant recipients was significantly more in the multiple artery group as compared to the single artery group (339 ml ±292 and 130.7 mL ± 44.8; p = 0.03). The recipient renal function was similar for both the groups at postoperative day 7, 1 month and at 1 year.
|Single artery (n = 150)||Multiple artery (n = 12)||p value|
|Donor outcome||Warm ischemia time (mins)||4.12||4.25||0.65|
|Recipient outcome||Mean blood loss (mL)||130.73||339.58||0.03|
|Mean creatinine 1 week (μmol/L)||112.76||118.83||0.52|
|Mean creatinine 1 month (μmol/L)||114.22||110.33||0.51|
|Mean creatinine 1 year (μmol/L)||117.11||123.83||0.48|
Our data supports that the laparoscopic approach to donor nephrectomy in the presence of multiple renal arteries can be safely performed with adequate laparoscopic experience.
There is an increasing discrepancy between supply and demand in renal transplantation. Utilization of pediatric deceased donor kidneys has been introduced to address this problematic. In this study, we reviewed cases of en bloc and single pediatric kidneys transplanted to adults and evaluated allograft long-term function and survival.
From April 1990 through February 2009, 60 adult recipients received deceased donor renal transplants from donors aged 10 years or less in a single centre. Eleven cases were performed with en bloc kidneys (EBK) and 49 cases were done with single separated allograft (SK). Recipient and donor demographic data, operative parameters, complications, long-term renal function, graft and patient survival were analyzed.
Donor age and donor weight were lower in the EBK group: 4.4 vs. 7.1 years (p < 0.001) and 16.1 vs. 27.6 kg (p < 0.0001) respectively. Recipient characteristics were comparable on all points. Cold ischemia time was shorter in the EBK group (16.1 vs. 21.6 hours, p = 0.02). Regarding complications, acute rejections were more frequent in the SK group (57% vs. 18%, p = 0.04). Thrombosis rate and urologic complications were similar between the two groups. However, we found a trend for a higher transplant renal artery stenosis rate in SK group (26% vs. 9%). No allograft was lost following TRAS or related treatment complication. Both groups presented a good long-term renal function but eGFR was higher at all time points for the EBK group (75±19 vs. 60±17 mL/min/1.73m2 at 1 year and 83±20 vs. 63±18 mL/min/1.73m2 at 5 years). Graft survival was 100 vs. 96% at one year, 100 vs. 87% at 5 years and 100 vs. 81% at 10 years for the EBK compared to the SK group respectively (log rank test, p = 0.17 ). Finally, patient survival was similar between the groups (1-year, 5-year and 10-year patient survival was respectively 100 vs. 98%, 100 vs. 91% and 100 vs. 85%).
Pediatric donor kidney transplant is a viable option to address shortage of organs. EBK transplant allowed utilization of small donors with excellent outcomes. Despite a higher rate of rejection and TRAS, SK transplant achieved good function and survival with the potential advantage of giving access to transplantation to more listed-patients. This article did not assess the optimal selection criteria that should be used to decide between EBK and SK. Future studies should try answering this important question.
One of the most frequent complications after radical prostatectomy (RP) is bladder neck contracture (BNC) that occurs in up to 32% of patients. Several treatment options for BNC have been proposed, but none reached a consensus and success rates are disappointing. Mitomycin, by inhibiting fibroblast proliferation, decreases scar formation. It was already used as an anti-scarring agent treating successfully glaucoma, tracheal and oesophageal strictures. In urology, 0,1 mg of Mitomycin had been used after laser incision to treat anterior urethral stricture. The objective of this study is to assess the safety and efficacy of Mitomycin in recurrent BNC.
This study was approved by our Institutional Review Board committee. Recurrent BNC was defined as the inability to pass a 16 French cystoscope through the stricture after at least one previous treatment. The initial workup included history, physical examination, urodynamic studies, urinalysis and urine culture. After informed consent, 0.1 mg of Mitomycin diluted in 2 mL of normal saline was injected submucosally at 3, 6 and 9 o’clock positions and the BNC was then dilated with «S shape» dilatators up to 18–20 Fr under sedation. A 16 Fr urinary catheter was left in place for 3 days. Follow-ups at 2, 6 and 12 months were scheduled (urinalysis, urine culture and cystoscopy). If a recurrence occurred, patients were offered another treatment option.
From March to July 2009, ten patients had recurrent BNC after RP diagnosed in the workup of urinary incontinence. Nine patients had retropubic and 1 had laparoscopic RP. The mean age was 67 years old [59–75]. The mean time between RP and diagnosis of BNC was 39 ± 7 months [2–180]. Patients had an average of 2 treatments for their BNC before Mitomycine [1–9]. All patients had dilatation, 2 had laser incision and 2 had cold knife incision. Eight patients showed no recurrence of BNC at 2 months follow-up cystoscopy. Of those recurrences, one had 9 and the other had 4 previous treatments. Five patients completed 6 months of follow-up and they were still stricture free. No adverse event was reported.
Preliminary results of this case series showed an 80% success rate at 2 months post Mitomycin injection and dilatation for recurrent BNC after RP. It seems promising and there is no associated adverse event. However, longer follow-up and further studies are needed to access its use and long term efficacy in BNC following RP.
Postprostatectomy incontinence (PPI) is a significant morbidity associated with prostate cancer surgery. Placement of a trans-obturator bulbourethral male sling (TOMS) (Advance Male Sling, American Medical Systems, Minnetonka, MN) has shown excellent results with minimal morbidity. One issue has been management of sling failure. We address the method and results of sling excision and replacement following initial failure.
A retrospective chart review of patients undergoing excision and replacement of an TOMS at our institution was performed. A standardized surgical method similar to the described original placement method was used. The centre portion of sling material was dissected off the corpus spongiosum and excised prior to replacement of the sling. Several factors including time to treatment of incontinence, time to initial failure, potential reasons for failure and end outcomes were identified.
Replacements were identified, with an average age of 66.1 yrs (47–84). The average time between treatment of the malignancy and first incontinence procedure was 21.2 months (12–40). The mean time to sling replacement was 205.6 days (3–600). Six of the twelve patients identified a period of postoperative strenuous activity associated with recurrence of incontinence. Persistent incontinence in one was recognized as inappropriate anatomical positioning. Four patients were completely dry at last follow up with no other intervention. Another patient was dry with subsequent Coaptite injection. Seven patients were socially continent (</=1pad per day). Two other patients had subsequent artificial urinary sphincter placement. No mesh erosions, hemmorhage or mesh infections were identified after repeat TOMS.
While placement of a TOMS to treat PPI is effective, failures do occur. Nonetheless, repeat placement of TOMS after excision of the previous mesh is a viable option for patients with persistent or recurrent bothersome incontinence.
Radical prostatectomy remains a common treatment for locally confined prostate cancer; however, complications of erectile dysfunction, incontinence and bladder neck contracture (BNC) persist. While active surveillance with delayed intervention is a treatment option, many patients still choose invasive therapies. When a patient suffers a significant complication that requires surgery, such as an artificial urinary sphincter (AUS) or a penile prosthesis, they often wonder if they could have selected a less invasive therapy or even observation. This review of radical prostatectomy specimens was initiated to investigate the relationship between pathology and complications. Additionally, we retrospectively consider how many patients may have been candidates for active surveillance based on their pathologic review.
All patients who required AUS, male slings, penile prosthesis or complex management of bladder neck contractures including open repair were identified. All patients had undergone a radical prostatectomy prior to their complication at sites throughout North America. Pathology was available from the Calgary Prostate Database from 2000 to 2010 to allow for analysis. Those patients who had suffered their complication as a result of external beam radiotherapy, cryotherapy, brachytherapy or HIFU were excluded.
We identified 80 patients who had required surgical management of post-prostatectomy complications. Pathologic review was then undertaken and identified 35 patients who had pathologic specimens from both TRUS biopsy and radical prostatectomy. Of these patients, 16 had an AUS, 16 had a male sling and a remaining 3 had complex management of their bladder neck contracture or refractory overactive bladder. Of the 35 patients, 20% had bladder neck contractures requiring at least a dilation and 20% of patients had required radiation in addition to radical prostatectomy. Review of pathology identified an average pre-operative PSA of 6.32 and gland volume of 49.6 grams. Postoperative pathologic review showed that 40% were Gleason 6, 54% were Gleason 7 and 6% were either Gleason 8 or 9. Average tumour volume was 12.4% of prostate volume. In this population, 37% had positive surgical margins and 8.6% had positive seminal vesicles. Twenty-three percent of patients may have been candidates for active surveillance.
Active surveillance must be considered as a treatment option in patients with low grade prostate cancer. In a population of men who have suffered a significant complication from radical prostatectomy, pathologic review identifies a large number of patients who have low grade disease and even clinically insignificant cancers.
The last generation of midurethral slings, the tension-free vaginal tape system (TVT-Secur™, Gynecare, Ethicon, NJ, USA) was introduced in 2005 in an attempt to lower the complication rates. There are two surgical techniques currently used either the ‘hammock’ or the ‘U-method’ technique. With the latter, the sling is tightened as to create a ‘pillowing effect’ on the urethra until obtaining a negative stress test. Short term current results of this surgical option seem promising, however, no study ever reported on the voiding function after its implantation. This is a retrospective, clinical study in which the main objective is to evaluate if this method creates an obstructive pattern on pressure-flow study 12 months after the surgery.
These are preliminaries data on a population which consisted of 34 women operated between October 2007 and April 2009. The implantation of the TVT-Secur™ system was done under local anesthesia by a single surgeon, using the ‘U-Method’ technique. Patients were evaluated before and 12 months after the surgery with regard to different urodynamic findings including uroflowmetry (UFM), postvoiding residual volume (PVR), filling cystometry (CMG), pressure-flow studies and valsalva leak point pressures (VLPP).
To date, 20 out of 33 patients have completed their 12-month urodynamic evaluation. The mean (± standard deviation [SD]) age of the population was 63 (± 9) years old, 21.2 % (7/33) complained of genuine SUI and 18.2 % (6/33) had undergone a previous anti-incontinence surgery. At 12 months postoperative, median satisfaction rate was 98% (range 95–100), the subjective cure rate was 82% (22/27) and 11% (3/27) of the patients reported a significant improvement. The objective cure rate (defined as no leakage at all during the VLPP) was 55% (11/20) while 40% (8/20) of the subjects were objectively improved (defined as leakage which occurred at a higher volume than preoperative VLPP). UFM and PVR were not affected by the surgery. The pressure-flow studies were not obstructed in all evaluated subjects (16/16). No patients developed de novo urge incontinence at 12 months.
Midurethral TVT-Secur™ slings represent an appropriate option for patients suffering from SUI. They are not associated with any significant bladder obstruction nor long term urinary retention while having very similar cure rate as the other midurethral slings. To our knowledge, this is the first study comparing preoperative and postoperative urodynamic findings in patients with ‘U-method’ TVT-Secur™ midurethral sling.
There have been over 40,000 sacral neuromodulation (SNM) systems implanted worldwide. Published reports to date have been limited to case series or randomized controlled trials with a few hundred patients at most, but with very high success rates. Our aim was to report patterns of use and outcomes of SNM in the general community.
A 5% random sample of United States Medicare beneficiaries from 1997 to 2007 and the entire Ingenix from 2002 to 2007 were the data source. CPT codes were used to identify all procedures, and ICD-9 diagnosis codes were used to identify the indication. Successful test stimulation was defined as a percutaneous or surgical lead placement followed by a battery implant at a later date.
In the Medicare population there were 358 patients who received percutaneous tests and 1132 a 2-stage (permanent) lead placement; 91.3% of patients were white and 73.6% were female. Of all percutaneous tests, 45.8% were considered to be successful. Of those with a 2-stage (permanent) test lead 62.7% failed and were not implanted with a battery. In the multivariate analysis there were greater odds of success in females compared to males overall (OR 1.86, 95% CI 1.38–2.51). When comparing those aged 65–75 to those over 75 there were inferior results in the younger group in the perc test (OR 0.11, 95% CI 0.054–0.22), but the opposite in the two staged (OR 2.04, 95% CI 1.49–2.79) and the overall odds ratio was not significant when combining both samples. There were no differences in success by race or by diagnosis except those with “dry” OAB overall fared worse compared to “wet” OAB (OR 0.73, 95% CI 0.55–0.97). In the privately insured there were 266 percutaneous and 794 two-staged procedures. The sample was 81.3% female, 82.2% were under the age of 65 and 62.7% were Caucasian. Percutaneous procedures were only successful in 24.1% of cases, whereas 50.9% of all two stage procedures resulted in a battery implant (p < 0.0001). On multivariate analysis women were 1.99 times more likely to be successful overall (95% CI 1.4–2.8) and those with a diagnosis of neurogenic bladder were 0.38 times less likely that OAB wet to succeed (95% CI 0.20–0.73).
SMN is far less successful than quoted in published literature. Females have better success than males. These findings suggest the need to counsel patients realistically about their chances of success with such a procedure.
Until the advent of mid-urethral synthetic slings, autologous fascia pubovaginal slings (PVS) were regarded as the treatment of choice for primary and secondary surgical management of female stress urinary incontinence (SUI). The management of failed synthetic slings or recurrent SUI following erosion or fistulae associated with synthetic slings is problematic. This retrospective analysis is a review of current experience with management of complex SUI with PVS.
A retrospective chart review of patients undergoing PVS was used to assess patient characteristics, indication for the sling, and preoperative urodynamic features, and continence outcomes.
This study comprises of 34 females, with an average age of 57 (33–77) years who underwent a rectus fascial PVS. Seven patients had concomitant surgery for cystocele, rectocele or urethral/vesical fistula repair. Preoperative mean pad usage was 6 pads/day. There were 31/34 patients who were selected for a PVS due to severe injury to the urethral sphincter: eroded midurethral sling (10), failed midurethral sling (6), operative or traumatic urethral injury (6), previous failed pubovaginal sling (4), urethral diverticulectomy (3), obstetrical urethral trauma (1), and previous pelvic radiation (1). An average of 2 (0–4) surgical incontinence procedures had been carried out before the PVS was performed. Preoperative urodynamics were completed for 29 of the patients. Capacity was <250 mL in 3 patients, and detrusor overactivity was demonstrated in 8 patients. Valsalva leak point pressures were <60 cmH2O for 5 patients, 60–90 cmH2O for 11 patients, and >90 cm H20 for 13 patients. Mean urodynamic peak flow was 20 (2–44) mL/sec. After a mean follow-up of 15 months, 72% of the patients were using ≤2 pads per day. Intermittent catheterization was required for 4 patients temporarily, and 4 patients continue on intermittent catheterization. Mean peak flow was 11 (3–20) mL/sec. In follow-up, 50% had urinary frequency of <1.5hrs, 32% had mild urgency, and 42% had bothersome urgency.
The PVS is now rarely used as first line therapy for SUI. It is primarily used as a salvage procedure for patients with previous urethral surgery, failed mid-urethral sling(s), and complex and severe SUI. Outcomes in this population are reasonable considering the severity of the underlying problems.
Urinary frequency is an extremely troublesome symptom for many women and its causation is relatively poorly understood. This study attempts to identify urodynamic indices that may play a role in patient-reported frequency severity. In this study, we investigated the relationship between patient-reported urinary frequency versus maximum cystometric capacity (MCC), first sensation of bladder filling (FSBF) and detrusor overactivity observed on cystometrogram in women. The relationship between patient reported frequency and nocturia was also investigated.
We have electronic charts on all patients who have undergone Conventional Urodynamic Studies from 1996–2007 at our institution contained in an urodynamic (UD) database. Using this database, MCC, volume at FSBF, detrusor overactivity and patient reported nocturia were cross-referenced with the degree of frequency reported by women. Frequency was divided into normal, 2–3 hrs, 1 hr and <1hr. Mean and standard deviation for MCC, FSBF and nocturia were then determined for each level of frequency. A one-way ANOVA (p < 0.05) was applied to determine statistical significance. Bladder overactivity for each group was described as a total number and as a percentage.
There were 2532 consecutive patients identified in the UD database. The numbers of patients for each frequency group (normal, 2–3 hrs, 1 hr, and <1 hr) were 346, 875, 852, and 459 patients, respectively. MCC, volume at FSBF and patient reported nocturia all significantly correlated with increasing severity of patient reported frequency (p < 0.0001). In addition, bladder overactivity increased with increasing severity of frequency.
This is the first large study to demonstrate that multiple factors may play a role in patient-reported frequency. Increasing severity of frequency is associated with decreased bladder capacity, earlier first sensation of bladder filling and increased prevalence of detrusor overactivity. Not surprisingly, these same factors are likely to play a role at night resulting in increased nocturia in the patient with frequency. Understanding that multiple variables are involved and interrelated may allow us to more thoroughly treat our patients
The presentation of female periurethral mass is rare in urological practice, with few series reported. We herein share our experience with their diagnosis and management.
A prospective case series was maintained from clinical diagnosis to complete follow-up by a single surgeon (KVC). All cystic and solid masses were included. Simple condylomata, caruncles and urethral prolapse were excluded.
Forty-one women were evaluated over a seven-year period (2002–2009), and complete follow-up is available on 36 (88%). Mean age was 41 with a mean follow-up time of 9 months. No masses were discovered incidentally. Most patients (92%) presented with a bothersome introital mass, 45% each with dyspareunia and urethral discharge, 29% with obstructive voiding and 22% with dysuria. A history of urinary infections was elicited in 24% of women, and stress incontinence (SUI) in 22%. Symptoms did not correlate with final diagnosis. All women underwent clinical history, physical exam and flexible cystourethroscopy. Clinical evaluation was accurate in the majority of cases (89%). There were 19 patients (46%) who underwent MRI, which includes all but 2 patients with a suspected or potential diverticulum or solid mass proximal to the meatus. MRI diagnosis correlated with final diagnosis in 15 cases (79%), added to the preoperative diagnosis in 2 (11%), and was considered useful overall for diagnosis or surgical planning in 10 (53%). Thirty patients (83%) had cystic and 6 (17%) solid masses at final diagnosis. To date, no malignancies have been encountered. One Skene’s gland abscess has recurred, 1 patient following excision of Skene’s gland diverticulum has developed stenosis requiring dilatation, and two cases of latent SUI have required further surgery. No other recurrences or complications have been observed.
|Type of mass at final diagnosis||Clinical diagnosis||Final diagnosis||Management||Outcome|
|Cystic (30)||Skene’s gland abscess (11)||Skene’s gland abscess (11)||Simple excision||Success (10)|
|Skene’s gland diverticulum (2)||Skene’s gland diverticulum (2)||Simple excision||No recurrences|
Urethral stenosis (1)
|Urethral diverticulum (9)||Urethral diverticulum (9) [8 with inflammatory change, 1 with ulceration, 1 with nephrogenic adenoma, 2 were recurrent lesions]||Excision with layered closure only (5)|
Martius flap interposition (4)
Pubovaginal sling (2)
Latent SUI (1)
|Periurethral cyst NOS (4)||Simple cyst (3)||Simple excision (8)||No recurrences|
Latent SUI (1)
|Gartner’s duct cyst (4)||Gartner’s duct cyst (3)|
|Solid (6)||Urethral diverticulum||Leiomyoma||Excision +/− layered closure||No recurrences|
|Soft tissue mass (3)||Leiomyoma (2)|
|Fibroepithelial polyp (1)|
|Condylomata||Urethral epitheliod squamous hyperplasia|
|Urethral carcinoma||Giant condyloma|
After appropriate history, physical exam and cystourethroscopy most women can undergo successful surgical management of periurethral masses. Preoperative imaging should be used selectively: It is considered useful for surgical planning but should not be relied upon for definitive diagnosis. Our bias is toward surgical removal given the diagnostic uncertainty in some cases and the small but potential risk of malignancy reported by other authors. Careful dissection is critical to discern diverticula, and complete excision mandatory to avoid recurrence. Complications of surgery are minor and uncommon.
To determine proportion of OAB patients potentially at risk for adverse CNS events by assessing pre-existing CNS comorbidities.
This retrospective cohort study used the GE Centricity EMR database. OAB patients were identified by ICD-9 codes or a prescription between 01/01/1996 to 03/30/2007 for an OAB antimuscarinic agent. OAB patients with 13 months of continuous eligibility pre and post index date formed the OAB cohort. Based on the presence of a pharmacy claim for an OAB antimuscarinic agent, the OAB cohort was stratified as treated or untreated. A random sample of age and gender matched patients with no diagnosis of OAB, urinary bladder dysfunction, or pharmacy claim for an OAB antimuscarinic agent formed a non-OAB control cohort. During 6 months before OAB diagnosis/treatment, CNS co-morbidity as measured by biologic measures, CNS diagnoses, and use of concomitant drugs with CNS effect and antimuscarinic effect (i.e. drugs other than those used for OAB treatment) were assessed across the cohorts using t-tests or chi-square where appropriate. Results: OAB patients (N:41,440; 83.6% women; median age 65 years), as compared to non-OAB patients (N:77,272; 83.2% women; median age 64 years), were more likely to have CNS comorbidities (45.4% vs. 29.0%; p < 0.001) such as neurotic disorders, personality disorders, and other nonpsychotic mental disorders (35.3% vs. 22.5%, p < 0.001), use medications with CNS effects (33.3% vs. 20.0%; p < 0.001) and antimuscarinic effects (39.6% vs. 25.4%; p < 0.001). In treated vs. untreated OAB patients, use of medications with CNS effects (35.3% vs. 24.8%; p < 0.001) and antimuscarinic effects (41.5% vs. 31.8%; p < 0.001) was higher for treated OAB patients.
Pre-existing CNS comorbidities were more prevalent in OAB patients than in non-OAB patients. Use of medications with CNS and antimuscarinic effects was more prevalent in those who received antimuscarinic treatment than in patients not receiving treatment.
Re-operation rate of the sacral neuromodulation (SNM) remains a concern. There are very few reports addressing this issue. We are reporting a 14-year experience with SNM from our centre.
Retrospective review of the patients’ data was performed to assess incidence and cause of surgical re-intervention after SNM implant between 1994 and 2008 in our centre.
There were 96 SNM devices implanted in 88 women (91.7%) and 8 men (8.3%). Mean age at implantation was 45 years (SD ± 12.5). The indications for implantation were painful bladder syndrome/interstitial cystitis (PBS/IC) (47.9%), urge urinary incontinence (UUI) (35.4%) and idiopathic urinary retention (IUR) (16.7%). The explantation rate was 20.8% and the median time to removal was 18.5 months (SD ± 31.7). The PBS/IC had the shortest time to explantation with mean of 15 months (p = 0.02). The reasons for the explantation were poor result in 12 patients (12.5%), painful stimulation in 6 patients (6.25%) and radiation of the stimulation to the leg in 2 patients (2%). The median long-term follow-up was 50.7 months (SD ± 38.1). The long term success rate was 87.5%, 84.8% and 73 % in the IUR, UUI and PBS/IC respectively (p = 0.6). In all, 39% of the patient needed revision of the SNM implant. The revision rate was highest in IUR (56%), while in UUI it was the lowest (32%). The main reason for revision was loss of stimulation in 24 procedures (58.5%). Other reasons includes pain from the pulse generator in 7 procedures (17%), painful stimulation in 5 procedures (12.2%) and radiation of the stimulation to the leg in 5 procedures (12.2%). There was drop in the rate of revision with the introduction of the tined lead technique from 50% (lead model 3092) to 31% (lead model 3893); however, this difference was not statistically significant (p =0.1). The battery was changed in 8 patients and the mean battery life was 101.8 months (SD ± 23.4).
The SNM is a minimal invasive procedure with a very good long-term outcome. Re-operation rate reduced with improvement in surgical technique and equipment.
To evaluate the long-term efficacy and tolerability of Pentosan Polysulphate Sodium (PPS) in the treatment of PBS/IC.
This is a single institution, retrospective study to evaluate the clinical efficacy of PPS as treatment for the cases of PBS/IC for the period of 1994 till 2008. We have included all patients with bladder pain symptoms and either frequency, urgency or nocturia in the absence of urinary tract infection and any other pathology as per ICS definition. All patients had glomerulation with cystoscopic hydrodistention under general anesthesia. The primary end point of this study is the overall improvement on the global response assessment scale (GRA).
Based on the inclusion criteria, 271 patients were eligible for the study. Most of the patients were female (90%), and the mean age at presentation was 45.5 year (SD ± 13.9). The average duration of symptoms was 28.5 month (SD ± 25.4).The average maximum cystometric capacity was 251.3 ml (SD ± 134.4), while the average maximum cystoscopic bladder capacity under general anesthesia was 659.1 ml (SD ± 147.4). The cough leak test was positive in 30 patients (11.1%). Detrusor overactivity on filling cystometry study was found in 39 patients (14.4%). With a mean follow up of 22 month (SD± 28), 147 patients (54.2%) reported over 50% improvements in there bothered symptoms on the GRA scale. There was mild improvement in additional 55 patients (20.2 %). Ninety-three patients (34.3%) decided to stop taking the medication for various reasons. The most common reason to stop the medication was poor response in 45 patients (16.6%). Others include drug side effect in 30 patients (11.1%), resolution of the PBS/IC symptoms in 11 patients (4.1%) and financial reason in 6 patients (2.2%). The side effects include stomach upset in 23 patients (8.5%), headache in 6 patients (2.2%), hair loss in 3 patients (1.1%), hypersensitivity in 3 patients (1.1%), and increase in liver enzyme in 2 patients (0.7%). Patients with history of detrusor overactivity or positive cough leak test during the urodynamic study were predictor of poor outcome of the PPS in the management of PBS/IC with p values of 0.037 and 0.035 respectively.
The Pentosan Polysulphate Sodium is an effective oral therapy to control the symptoms of the PBS/IC with good long term efficacy and tolerability. More than 65% of the patients continued to take the medication with mean follow up of 22 months.
Vesicovaginal fistulas (VVFs) may be managed by a transabdominal (TA) or transvaginal (TV) approach. With increasing urologic training in transvaginal surgery, there has been a movement towards transvaginal repairs whenever possible. The objective of this study was to evaluate our experience with VVFs over a 7 year period following the arrival of a fellowship-trained female urologist.
We performed a retrospective chart review of VVFs presenting between April 1, 2002 and Dec 31, 2009. All final TV closures were performed by a single surgeon (KC) while the TA repairs were spread amongst a broader group of surgeons.
31 cases were identified. Average age at surgery was 50.5 years (range 27–84 years). Follow-up ranged from 3–222 weeks (median 8). The etiology of 26 (84%) was hysterectomy [19 abdominal (73%), 7 vaginal (27%)]. The remaining 5 fistulas were caused by radiation (1), birth trauma in a developing country (1), uterine rupture and caesarean section (1), and bowel surgery (2). 6 VVFs occurred after hysterectomy complicated by intraoperative cystotomy repaired by the operating gynecologist. At the time of referral to urology 6 patients (19%) had prior failed repairs: 4 patients with 1, 1 patient with 2, and 1 patient with 4 prior repairs. Ultimately, 20 fistulas (65%) were repaired transabdominally and 11 (35%) transvaginally. The time to surgical repair ranged from 2 weeks to 30 years. Compared to TA repairs, TV repairs were associated with shorter hospital stay (p = 0.005), and there was a trend toward shorter operative time (p = 0.09) and blood loss (p = 0.07). Suprapubic catheters (SPC) were placed at the time of 13 TA repairs (65%) versus 1 TV repair (9%). One patient (9%) following TV repair developed postoperative pelvic pain syndrome, while 8 patients (40%) undergoing TA repairs experienced complications [small bowel obstruction, bladder infection, prolonged postoperative pain, incisional hernia, enterotomy, prolonged ileus, prolonged pain secondary to SPC (2)]. No patients remain with fistula at the time of reporting.
The majority of VVFs can be managed via a TV approach employing tissue interposition. These repairs are associated with reduced hospital stay and lower morbidity, and a trend toward lesser blood loss and operating time when compared to TA repairs. Suprapubic catheters can add morbidity, and are not necessary for successful outcome in uncomplicated repairs.
The use of buccal graft onlay has been shown to be an excellent option for long bulbar urethral strictures. A narrow lumen may preclude the use of an onlay alone, and in these instances an augmented anastomosis is needed. We therefore performed this study to evaluate the outcomes and complications of dorsal buccal graft augmented anastomosis urethroplasty (BGAA) for anterior urethral strictures.
Seventy-six patients underwent BGAA between 2000–2009. Their charts were retrospectively reviewed. Failure was defined as recurrent stricture requiring intervention. Three weeks post surgery, patients underwent voiding urethrography. Flexible cystourethroscopy is performed 6 months after surgery. Patients are then followed yearly.
Mean age was 44 years. Follow-up averaged 49 months (range 3.6 to 108). Stricture etiology was idiopathic in 39/76 (51%), perineal trauma in 13/76 (17%), instrumentation in 9/76 (12%), non-specified trauma in 7/76 (9%), post hypospadias surgery in 4/76 (5%), post infectious in 3/76 (4%), radiation for local urethral cancer in 1/76. Mean stricture length was 6cm (range 2–15cm). There were 70/76 (92%) who had previous urethral procedures, including dilation 54/76 (71%), urethrotomy 46/76 (61%), >/= 2 prior procedures 52/76 (68%), and urethroplasty 20/76 (26%) before referral to our centre. Two buccal grafts were used on 20/76 (26%) of patients; one graft was used on 56/76 (74%); 72/76 (95%) of repairs were successful and 4/76 (5%) failed. Three patients underwent urethrotomy and are free from recurrence. One patient underwent dilation and is free from recurrence. One other patient has a wide caliber recurrence that is currently being monitored. Significant perioperative complications included one pulmonary embolus (this patient was found to have a coagulopathy), one superficial venous thrombosis and two postoperative fevers presumed to be febrile urinary tract infections.
Dorsal buccal graft augmented anastomosis for anterior urethral strictures has excellent results with a 95% success rate. Continued surveillance of these patients is needed to confirm persistent durability.
For tissue-engineering of urothelial cell-matrix implants appropriate biodegradable matrices are a continued challenge concerning biocompatibility, stability, and degradation in vivo. To overcome these problems, autologous urothelium generated in vitro without matrices or scaffolds might be an alternative. However, matrix-free urothelium (MFU) is unstable and thus has to be stabilized for reconstructive surgery, e.g. of the urethra. Aim of the study was to prove 1) fibrin glue as a stabilization factor concerning influence on the viability of fibrin glue-sprayed human urothelial cells (HUCs) and for surgical manipulation of MFUs sprayed with fibrin glue and 2) to investigate the outcome of transplanted MFUs sprayed with fibrin glue in a pilot nude rat model.
The influence of fibrin glue on the viability of proliferating and confluent monolayer HUC cultures was analyzed with the metabolic WST-1 assay. Seven enzymatically detached MFUs established from three different primary HUC lines were sprayed with fibrin glue and investigated for mechanical stability. For verifying the outcome in vivo, MFUs were sprayed with fibrin glue and sutured on the musculus rectus abdominis of athymic rats. For in vivo tracking, HUCs have been labelled with fluorescent PKH26 cell linker. Transplants were examined histologically and immunologically for epithelial pancytokeratin (AE1/AE3) after 7 days.
Viability of fibrin glue-sprayed HUC cultures both in the proliferative and confluent phase reached up to 62% and 89%, respectively, of the control group at day seven. MFUs sprayed with fibrin glue after detachment demonstrated a good mechanical stability compared to unsprayed MFUs. The fibrin glue-sprayed MFUs were handled well with surgical instruments. In performed cryosections of MFUs at day 7 after transplantation the integration in the target tissue and the epithelial phenotype could be demonstrated. Fibrin glue was nearly degradated. There was no inflammatory reaction.
Clinical application of tissue-engineered MFU requires stabilization factors due to its mechanical instability. Spraying with fibrin glue enhanced the mechanical stability of MFUs so that they could be well manipulated with surgical instruments. The impact of fibrin glue on the vitality of HUCs was considerably low. These findings are encouraging and suggest fibrin glue as biocompatible stabilizer for urothelial constructs generated in vitro. The study will be extended to develop a myourothelial flap in a nude rat model for reconstructive ureteral and urethral surgery.
Search of vesicoureteral reflux (VUR) is part of the standard work-up of children with febrile urinary tract infection (UTI). However, VUR can present later in life and should be investigated in cases of recurrent pyelonephritis. Herein we prospectively evaluated the efficacy of endoscopic injection in the adult population.
Between December 2005 and September 2009, 27 post-pubertal patients (3 males, 24 females) were treated endoscopically with subureteral injection of polydimethylsiloxane (13) or hyaluronic acid (14). A total of 41 refluxing units were injected (14 bilateral). Median age was 23 years (12–65 years). The VUR was evaluated as grade I in 5 ureters, II in 28, III in 7 and IV in 1. Indications for surgery were recurrent pyelonephritis in all patients except one with dorsal pain during voiding. Renal scars were present in 15 renal units (37%) and duplex systems in 6 (15%). Five patients (12%) had previous ureteral surgeries (2 reimplantations). The procedure was performed by a single surgeon on an outpatient basis, with the patient under general anesthesia. Patients were followed with renal ultrasonography and voiding cystourethrography were repeated as needed based on the clinical evolution.
VUR was corrected in 38 (93%) of 41 ureteral units. Of the 3 failures, one patient had a large Hutch diverticulum and another one had previously undergone ureterocele incision. All of the failures were injected with hyaluronic acid. Therefore success with polydimethylsiloxane was 100% and 87% with hyaluronic acid. De novo hydronephrosis appeared in 1 renal unit and obstruction was confirmed by MAG3-lasix. Temporary diversion with a double J stent was necessary. Hydronephrosis resolved after removal of the stent.
Subureteral injection is an effective treatment for VUR after puberty. In cases of recurrent pyelonephritis, imaging should be mandatory to detect scars and VUR because the endoscopic treatment is simple, non-invasive and gives a good success rate, comparable to the one reported for children.
There are many novel techniques to treat localized prostate cancer. Almost all use prostate volume as a cut-point to obtain better results. Imaging methods (computed tomography, magnetic resonance, ultrasound) may have a wide measurement variability between each other. We have compared reports of trans-rectal ultrasound (TRUS) and digital rectal examinations (DRE) with the actual dimensions and weight of prostate specimens after radical prostatectomy; other than the usual “ellipsoid shaped formula”, we also used a new “bullet shaped formula” for validation.
During 18 months, three dimensions (height, width and length) were obtained from 150 fresh specimens after radical prostatectomy and before formalin fixation. The prostate gland was also weighted. In this study, those values were compared with transrectal ultrasound measurements. Each TRUS measurement was compared to fresh specimen dimensions to evaluate which were more susceptible to errors. Clinical patterns were analyzed to verify the main reasons of error.
Median age was 61 years old. Gleason score 6 or 7 was observed in 44.7% and 42.0%, respectively. Clinical stage T1c or T2a was present in 88.7% of cases. Laparoscopic or open radical prostatectomy was done in 64% and 34% of cases, respectively. When evaluating the DRE data, there was a clear tendency by the clinician to overestimate small (<40 g) and underestimate big prostates (>60 g). The overall rate of precise measurements (error less than 10%) was 21.3%, 22.0% and 31.3% for DRE, TRUS (ellipsoid shaped formula) and TRUS (bullet shaped formula). The “bullet-shaped formula” got results closer to the actual volume when compared to “ellipsoid shaped formula” and DRE. The dimension with fewer errors was width. When correlating subgroups with error or not and clinical-pathological features (PSA, Gleason score, margins, extracapsular extension, clinical stage), no predictor for inaccuracy during TRUS could be identified.
The prostate measurements obtained using TRUS are often inaccurate. The height and length dimensions have a larger degree of error. The DRE tend to aggregate the cases between 30 and 60 g, under or overestimating the others. At least in prostate cancer set, we couldn’t determine any clinical factor as a predictor of inaccuracy during TRUS exams. In light of the findings, further caution is necessary when using prostate volume as main criteria to include or exclude non-surgical treatments as therapeutic choice for localized prostate cancer.
Acute reversible kidney injury (ARKI) secondary to bilateral ureteric obstruction (BUO) is not uncommon. Our goals were to describe the etiology and management in such patients identified between 2006 and 2009 and to compare the etiologies to a similar historical study (CMAJ 127:601, 1982).
Chart review was performed on 75 patients with renal injury secondary to BUO who were admitted to our hospital. Those with bladder outlet obstruction (7) or who refused intervention (1) were excluded. Fifty-two of the remaining patients had ARKI as defined by ≥33% reduction in SCr after intervention.
Eighty-three per cent of patients had BUO secondary to malignancy, 28% of these presenting for the first time. Prevalence of bladder cancer was increased (p = 0.04) and cervix decreased (p = 0.09) compared with the earlier study; prostate cancer was unchanged (p = 0.79). Most common cause of benign BUO was ureteric stones compared with retroperitoneal fibrosis earlier. There was no significant difference in the mean presenting and discharge SCr for the malignant (741±57 μmol/L and 223±19) compared with the benign group (721±162 and 205±40). All patients were treated initially with ureteric stents/nephrostomy tubes/ureteric catheters.
|Site||1982 (n = 38)||2010 (n = 43)||Etiology||1982 (n = 12)||2010 (n = 9)|
|Cervix||11 (29%)||5 (12%)||Retroperitoneal fibrosis||8 (67%)||2 (22%)|
|Prostate||8 (21)||11 (26)||Ureteric stones||2 (17)||5 (56)|
|Bladder||5 (13)||15 (35)||Ligated ureters||2 (17)||0|
|Colon||5 (13)||6 (14)||Other||0||2 (22)|
|Ovary||5 (13)||1 (2)|
|Other||3 (8)||2 (5)|
|Lymphoma||1 (3)||3 (7)|
Patients with ARKI secondary to BUO most likely have an underlying malignancy, often being diagnosed for the first time. In this group of patients, the prevalence of bladder cancer increased while cervix decreased. The cause for the former is unclear; the latter may be due to aggressive screening; however, a similar effect in men with prostate cancer was not seen despite the availability of PSA testing.
As training hours decline we are developing an OR curriculum to teach complicated procedures based on a modular design. This model has been employed by various disciplines, including MIS urologists for some time now. It has been shown to decrease time to proficiency without increasing complication rates. Central to our design is a web-based log where residents record their involvement for each predefined step in a given surgery (i.e., pelvic node dissection during RRP). They may choose from roles (i.e., 1st assist, performed independently, etc), and periodically attendings review their progress. Focus can be tailored to least attempted or most challenging steps. As steps are ranked by difficulty, they may also be matched to house staff of varying years. Data collected from the logs can then be used fine tune the training program at various levels. We have attempted to define resident ideas and expectations in regards to their current surgical experiences to assess whether the modular education would address their needs.
Residents of Dalhousie’s Department of Urology were surveyed to delineate the needs, learning styles and perceived deficiencies of our current teaching model.
Of our residents, 92% participated in our survey and were analyzed in respect to their training levels. Residents felt surgical competencies were most effective with mentor driven group learning, and with immediate/specific feedback. However, knowledge based competencies were self-learned, and clinical competencies were best learned in a group. Junior residents (PGY3 and below) felt repetition of basic skills (i.e. suturing) was most helpful, while concentrating on discrete steps of a procedure was most important to seniors. Prior to performing a procedure independently, residents were most comfortable if each step was familiar, and complicated tasks were broken down to key elements. In regards to their current training, most felt that time is a determining factor in level of involvement, and that specific feedback may be improved upon. Difficulties in reporting experiences gained from one rotation, often led to decreases in surgical involvement on their subsequent rotation.
In general our residents have shown attitudes and preferences to more structured OR experiences and formalized and frequent assessments by their attendings. We feel that by structuring our teaching within the OR, we will continue to provide appropriate surgical training, and a more consistent learning experience within the constraints of decreased cumulative surgical training hours.
With the growing frequency of small renal masses, the rate of partial nephrectomy is on the rise. Despite the increasing number of laparoscopic radical nephrectomies being performed, laparoscopic partial nephrectomy has not gained wide-spread acceptance. This is likely due to the steep learning curve necessary to perform the procedure. We have endeavored to create a high fidelity model of laparoscopic partial nephrectomy in order to reduce the learning curve. In making the model, we ventured to identify the resistance and tear strength of the renal capsule.
Using eight (8) fresh porcine kidneys, the tear strength was measured by placing a 2–0 vicryl in the upper pole and laterally attached to a strain gauge fixed within a standardized apparatus to apply traction force. The resistance of the renal capsule was measured using a commercial Durometer at ten points along the upper pole and ten points on the lateral aspect of the kidney. The same measurements were made on post-radical nephrectomy specimens (including the resistance of the tumour) and on a preliminary silicone model. The mean resistance and tear strength values from the specimens were calculated and student T-tests performed for statistical analysis.
The tear strength of the porcine renal capsule was significantly different between the lateral aspect (317 ± 8 g) and the upper pole (278 ±116 g); however, this was opposite to what was seen in the human kidney (242 ± 26 g in the lateral aspect vs. 286 ± 17 g in the upper pole). The resistance of the porcine kidney in the lateral aspect (61.7 ± 24.5 units) was significantly higher than the upper pole (44 ± 13.4 units). However the resistance in the lateral aspect (17.4 ± 2.8 units) and the upper pole (17.1 ± 2.3 units) of the human kidney was not different. The resistance of the tumour was significantly higher at 41.8 ± 9.2 units. The tear strength of the preliminary model was significantly higher than that seen in the porcine or human kidney 526 ± 51.2 g as was the resistance (35.7 ± 3.1 units)
There is a significant difference in the tear strength of the renal capsule in differing regions of the kidney. Also, the resistance of the renal capsule overlying a renal tumour is substantially higher than normal tissues. These characteristics will be used to increase the fidelity of our model and may also be the basis of studies into visuo-spatial haptics in surgery.
The application of minimally invasive technology has become increasingly common in urological training programs and clinical practice. However, there is little published data on the impact of this technology on urology resident surgical case volume. Our objective was to review surgical case data from all 12 Canadian residency programs to identify trends in resident exposure to minimally invasive and open surgical procedures over a 6 year period.
Every year, beginning in 2003, an average of 41 PGY 3–5 residents voluntarily self-reported surgical case data to a secure internet relational database (T-Res®). Accumulated data was anonymized, extracted and analyzed for the period 2003–2009 by measuring a set of 11 predefined index cases which could be performed in both an open and MIS fashion. [Nephrectomy(donor, radical, simple, partial), Prostatectomy (simple, radical), Cystectomy (radical, partial), Nephroureterectomy, Pyeloplasty, Adrenalectomy]
There were 78,897 cases recorded in the database over the study period by a total of 198 residents. Of these entries, 16,687 represented index cases. As a proportion of all index procedures logged by trainees, there was a significant increase in minimally invasive surgeries over the study period from 16% in 2003–04 to 33% in 2008–09 (p = 0.025). A significant decrease in the proportion of index cases performed with an open approach was also observed from 84% in 2003–04 to 67% in 2008–09 (p = 0.025). The majority of these shifts were secondary to the significantly increased application of MIS for Nephrectomies of all types (43–51%), Nephroureterectomy (34–75%), Adrenalectomy (47–72%), and Pyeloplasty (26–48%) (p < .001 for all). While there was a significant increase in MIS experience with radical prostatectomy (6.5%–18%, p < 0.0001) the majority of these were still taught in an open fashion during the study period.
Minimally invasive surgery constitutes an increasingly significant component of surgical case volume in Canadian urology residency programs. This has caused a reciprocal decrease in resident exposure to open surgery for some index urological procedures. These trends require ongoing evaluation in order to assess and maintain the integrity of postgraduate urological training.
Data from tertiary care centres suggest that the perioperative mortality (POM) after radical cystectomy (RC) is not different in septuagenarian and octogenarian patients compared to younger individuals. Conversely, population-based data state otherwise. We revisited this topic in a large contemporary population-based cohort.
Between 1988 and 2006, 12722 underwent radical cystectomy for urothelial carcinoma of the urinary bladder (UCUB) in 17 Surveillance, Epidemiology and End Results (SEER) registries. Of those, 4480 were aged 70–79 and 1439 were 80 and over. Univariable and multivariable logistic regression models tested 90-day mortality after radical cystectomy. Covariates consisted of gender, race, year of surgery, SEER registry, histological grade and stage.
Of all 12722 patients, 4480 (35.2%) were septuagenarian and 1439 (11.3%) were octogenarian. The overall 90-day mortality rate was 4% for the entire population, 2% for patients aged 69 years or younger, 5.4% for septuagenarian patients and 9.2% for octogenarian patients. In multivariable logistic regression analyses, septuagenarian (2.80; <0.001) and octogenarian (5.02; <0.001) age increased the risk of 90-day mortality after RC.
In this population-based analysis, POM was between 3 and 5-fold higher in respectively septuagenarian and octogenarian patients. This information needs to be included in informed consent considerations.
The cytoprotective chaperone heat-shock protein 27 (HSP27) and clusterin, as an inhibitor of apoptotic cell death, are shown to have an important role in progression, drug resistance and therapy response in various kinds of cancer. Single targeting was shown to increase chemo sensitivity and to have tumour inhibitory effects. The objective of this study was to show that the intravesically administered combination of the antisense oligonucleotides (ASO) OGX-011 and OGX-427, which is currently in early phase I clinical trial development for non-muscle invasive bladder cancer, may have additive or synergistic tumour inhibitory effects compared to a single treatment.
The human bladder tumour cell line KU7 luc that stably expresses luciferase was used in all experiments. In vitro, KU7 luc cells were transfected with ASO targeting HSP27 (OGX-427) and clusterin (OGX-011) in doses between 25–100nM and 100–400nM. Cell growth inhibition, cell cycle as well as protein and gene expression were analyzed. In vivo, using an established orthotopic bladder tumour model, KU7 luc cells were transurethral instilled into the urinary bladders of female nude mice. ASO was administered intravesically every other day for a period of 2 weeks. Monotherapy OGX-011 and OGX-427 was used in a concentration of 50uM each, as well as combination therapy at same doses each and non-targeting ASO (ScrB) as control. Tumour growth was observed by bioluminescence and mice were sacrificed on day 28.
In vitro, protein levels of clusterin and HSP27 were significantly decreased after single treatment with OGX-011 or OGX-427, as well as after the combination of both ASO. While both single treatments showed a dose-dependent growth inhibition, the combination of both treatments was superior to each of the single treatments. Cell cycle analysis showed a significant increase of the SubGo fraction for the combination treatment compared to single treatment. In vivo, intravesical treatment with the combination of OGX-011 and OGX-427 showed a significant inhibition of tumour growth (P < .05) compared to non-targeting ASO treatment.
The intravesical application of a combination of ASO targeting HSP27 and clusterin showed promising antitumour activity, providing pre-clinical proof of tumour inhibitory effects by an intravesical administered ASO combination treatment. Collectively, this data shows that further study of this combination is warranted in bladder cancer.
Fibroblast growth factor receptor 3 (FGFR3) mutations have been recently reported at a very high frequency in pTa bladder cancer (BC) whereas these mutations are rare in high grade muscle-invasive BC. pT1-BC comprises a heterogeneous group of tumours for which different management options are advocated depending on the risk of progression to muscle-invasive disease. We have determined the frequency of FGFR3 mutations in a group of primary pT1-BC and correlated the FGFR3 mutation to various histo-pathological variables and clinical outcome.
We included 132 patients from two academic centres (N=60 in Rotterdam / 72 in Toronto) with primary (first diagnosis) pT1-BC. Mean age was 68.7 years (SD: 9.9 y). An experienced uro-pathologist reviewed the slides for grade (1973 and 2004 classification systems) and determined if the tumour was micro-invasive (<0.5 mm; pT1m) or extensive invasive (multiple spots with invasion and/or >0.5 mm; pT1e). The FGFR3 mutation status was examined by SNaPshot analysis and correlated to pathological parameters. Kaplan-Meier statistics were used to analyze progression to >= pT2 disease.
Median follow-up was 6.5 years (range: 0.3–21.6 years). FGFR3 mutations were detected in 37/132 (28%) pT1-BC. The most frequent mutation in the FGFR3 gene (S249C) was observed 24 times whereas other FGFR3 mutations, R248C, G372C, Y375C, G382R were observed 5, 2, 5 and 1 time(s), respectively. The table shows that presence of a FGFR3 mutation was highly correlated with favourable disease characteristics in pT1-BC. Thirty-eight (29%) patients progressed. The FGFR3 mutation was associated with favourable clinical outcome, i.e., less progression (p-logrank = 0.041).
|FGFR3 mutant||FGFR3 wild type||p-value (chi-square)|
|Grade 1973||G2||25||31||< 0.001|
|Grade 2004||Low-grade||15||11||< 0.001|
The FGFR3 mutation selectively identifies pT1-BC patients with favourable disease characteristics. Further study may confirm that this molecular marker is able to select patients who will benefit from a conservative approach to their disease.
Currently, two classification systems for grade are advocated by our guidelines because the new WHO2004 classification system for grade has not been sufficiently validated against the old WHO1973 system with biological markers. We chose to evaluate the FGFR3 mutation as a marker for genetically stable non-muscle invasive (NMI) bladder cancer (BC) and aberrant expression of MIB-1, P53 and P27 as markers for genetically unstable NMI-BC.
The slides of 327 primary (first diagnosis) NMI-BC from two university hospitals (Rotterdam, the Netherlands and Toronto, Canada) were reviewed by one uro-pathologist for the WHO 1973 (G1, G2 and G3) and 2004 (low malignant potential (LMP), low-grade (LG) and high grade (HG)) classifications systems. FGFR3 status was examined by multiplex PCR-SNaPshot analysis. Expression levels of MIB-1, P53 and P27 were determined with standard immunohistochemistry. Cut-off-values for MIB-1, P53 and P27 were 25%, 10% and 50%, respectively.
Grade review resulted in 88 G1, 148 G2 and 91 G3 lesions (WHO1973) and 79 LMP, 102 LG and 146 HG lesions (WHO2004). FGFR3 mutations were detected in 187/327 (57%) of NMI-BC. Aberrant expression of MIB-1, P53 and P27 was found in 126, 99 and 72 NMI-BC, respectively. Stage pTa-BC had a FGFR3 mutation in 134/171 (78%) cases as opposed to 53/156 (34%) FGFR3 mutations in pT1-BC (Chi-square, p < .001). The table shows the relation of the 4 molecular markers with the 2 grading systems. In general, the FGFR3 mutation was associated with lower grades whereas MIB-1, P53 and P27 were associated with higher grades (Chi-square, p < .0001 for all). Moreover, the table shows that the WHO1973 G3 and G2 categories have a more aggressive biological potential than the WHO 2004 HG and LG categories. The G1 and LMP categories have a similar molecular profile.
Our results show that the introduction of the WHO2004 leads to higher grading implying a Will Rogers effect. Biological differences between the G3/HG and G2/LG categories were evident and support the continued joint use of both grading systems to guide clinical management of NMI-BC.
|FGFR3 mt (% of total)||MIB-1>25% (% of total)||P53>10% (% of total)||P27<50% (% of total)||Total|
|WHO1973||G1||78 (89)||5 (6)||2 (2)||3 (3)||88|
|G2||92 (62)||53 (36)||37 (25)||33 (22)||148|
|G3||17 (18)||68 (75)||60 (66)||36 (40)||91|
|WHO2004||LMP||67 (85)||5 (7)||2 (2)||3 (4)||79|
|LG||80 (78)||23 (23)||15 (15)||18 (17)||102|
|HG||40 (38)||98 (65)||82 (56)||51 (35)||146|
Current treatment options for nonmuscle-invasive bladder cancer following transurethral resection are of limited efficacy since up to 80% of patients develop recurrent tumours. Microtubules are one of the most successful targets in cancer therapy to date and the recent Phase I trial of intravesical docetaxel for treatment of nonmuscle-invasive bladder cancer refractory to BCG therapy has shown this to be a promising intravesical agent with minimal toxicity and no systemic absorption. The present work describes the development and in vivo evaluation of a mucoadhesive docetaxel formulation for intravesical bladder cancer therapy.
Mucoadhesive formulations based on hydrophobically derivatized hyperbranched polyglycerols (dHPGs) were synthesized and docetaxel was loaded into these by a solvent evaporation method. Four bladder cancer cell lines were treated with various concentrations of docetaxel formulations in vitro. Human KU7 bladder tumour cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumours were given a single intravesical instillation with PBS, Taxotere® (docetaxel from Sanofi-Aventis) or mucoadhesive docetaxel.
dHPGs are nanoparticles with hydrodynamic radii of less than 10nm and incorporation of docetaxel did not affect their size. The release profiles of docetaxel from these nanoparticles were characterized by a rapid release phase (55% drug release during the first 24 hours) followed by a slower sustained release phase. In vitro, all docetaxel formulations potently decrease bladder cancer proliferation. However, in vivo, mucoadhesive docetaxel was the most effective formulation to inhibit tumour growth in an orthotopic model of high-grade nonmuscle-invasive bladder cancer.
Our data show promising in vivo antitumour efficacy and provide preclinical proof-of-principle for the intravesical application of mucoadhesive docetaxel in the treatment of high-grade nonmuscle-invasive bladder cancer. Further research is warranted to evaluate its safety and efficacy in early phase clinical trials in patients refractory to standard therapy.
Elevated rate of metastatic stage at presentation may be indicative of delays in diagnosis and is usually considered as an adverse predictor of cancer control outcome. We examined the annual rates of diagnosis of metastatic germ cell tumours as well as the associated 5-year survival rates, in a large population-based cohort over a period of 20 years.
Between 1988 and 2006, 17080 and 12984 patients were identified with respectively seminoma and nonseminoma of the testis within the 17 SEER registries. Rates and proportions as well as 5-year overall survivals were recorded and analyzed.
Metastatic seminoma and nonseminoma was found in 2373 patients (7.8%). Of those, 500 (21%) and 1595 (79%) were metastatic at diagnosis. The rate of metastatic seminoma increased from 1.2 to 4.8% (Chi-square trend: p < 0.001) over the study span vs. 12.7 to 18.4% for nonseminoma (Chi-Square trend: p < 0.001). The median 5-year survival rate was 98% for both seminoma and nonseminoma. No differences were recorded in temporal 5-year survival rates (p = 0.08).
The rates of metastatic seminoma and nonseminoma at diagnosis increased over the study period. Therefore better detection strategies might require consideration. Nonetheless despite higher rates of metastatic disease at diagnosis the survival has not changed, which indicates excellent cancer control outcome.
The AJCC or TNM staging of penile carcinoma represents a standard and is widely used in clinical practice. We examined the ability of tumour grade that currently is not considered in the AJCC or TNM staging, to improve the prognostic ability of these two established staging schemes.
We relied on a population of 1577 penile carcinoma patients stages T1-4 N0-3 M0 who underwent an excision biopsy or partial or radical penectomy with or without a lymph node dissection. Separate Cox regression models were fitted for AJCC stages I to II (stage 0 not considered), T and N stages, as well as for T and N stages with tumour grade (grades I vs. II vs. III-IV). Harrell’s concordance index was quantified for each of the three tested schemes.
Overall, 194 patients died of penile carcinomas and the 5-year cancer-specific mortality rate was 16.1% (95% CI = 14.0 to 18.4%). The accuracy of AJCC staging in the prediction of cancer-specific mortality-free survival was 68.3% versus 70.0% for TN-based prediction (Mantel-Haenszel test, p < 0.001) versus 72.0% for T and N and grade-based prediction (Mantel-Haenszel test, p < 0.001).
The AJCC staging stratified non-metastatic penile cancer patients into three distinct categories versus 16 categories for the combination of T1-4 and N0-3 stages versus 48 categories for the combination of T1-4, N0-3 and grade 1–3 stage and grade combination. The prognostic accuracy of the AJCC staging schemes was the lowest versus an intermediate value for the TN-based scheme versus the highest for the TN and grade-based scheme. The superior prognostic ability of the TN and grade-based scheme suggests that grade should be routinely considered when the T and N stages are used for prediction of prognosis.
Testicular cancer has become the model for a curable neoplasm. Nearly 80% of the patients can be cured by surgery removing the residual masses after the cisplatin-based chemotherapy. However, there is continued controversy regarding the optimal treatment of patients with nodal metastases. While some investigators have reported relapse rates as low as 6.3% in patients with low-volume nodal disease managed expectantly, others have reported rates as high as 45%.
Between 1994 and 2008, three surgeons had operated 73 cases of post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) for metastatic residual germ cell testicular cancer. Our purpose was to analyze the indications, clinical features, patterns of recurrence, surgical complications, final pathology diagnosis in residual masses and clinical predictors of complications and viable cancer after chemotherapy. We have included patients with nonseminomatous histology, clinical stage II or III and residual masses post-chemotherapy treatment. To an objective analysis of surgical complications, we have used the Clavien classification ranging from I to V.
The majority of our cases were between 20 and 40 years old. Lymphovascular invasion was present in 32% of cases and 12% of cases had associated carcinoma in situ. Mixed germ cell tumour was the histology of orchiectomy in 59% of patients. The mean size of retroperitoneal metastasis before and after chemotherapy was 6.3 and 4.0 cm, respectively (p < 0.001). All patients received cisplatin-based chemotherapy. Ninety-two percent of patients were submitted to a complete bilateral dissection. Nerve-sparing procedure was not possible in 43% of cases. The complication rate was 38% but only 3 patients (4%) had grade IV complications and no one died. After review, 22% of patients had viable non-teratoma cancer on retroperitoneum and 41% had teratoma. Size of residual disease and the presence of fibrosis were predictors of surgical complications and non nerve-sparing procedures (p < 0.05). The mean follow-up was 47 months. After RPLND, we had only 2% of recurrence in retroperitoneum site and 8% of overall recurrence rate. The 5-year overall survival rate was 91%.
the PC-RPLND for testicular cancer is a relatively safe procedure. It is less likely to perform a nerve sparing surgery post chemotherapy than in primary procedures. There are still a large number of patients with viable cancer after chemotherapy, justifying surgical treatment of residual masses. The residual mass size and the presence of fibrosis are predictors to surgical complications and non nerve-sparing procedures.
Percutaneous nephrolithotomy (PCNL) is the gold standard therapy for large renal calculi. The optimal puncture site for collecting system access remains controversial, with many suggesting increased morbidity from supracostal puncture. We report a retrospective review of 318 consecutive PCNL cases over a sixty month time period performed by two surgeons in a teaching environment.
Perioperative data was collected on 318 consecutive PCNL cases performed for intra-renal nephrolithiasis from May 2004 to June 2009. Patient demographics, stone, operative, postoperative and follow-up data were collected. Complications were assessed using the Clavien system and stone outcomes were assessed with KUB x-rays and CT scans. Successful treatment outcome was defined as stone free or sand-like (1 mm or less) particles on CT scan.
Three hundred and eighteen patients undergoing PCNL in the prone-flexed position (57.9% male) with a mean age of 52.9 years (SD 14.4) and mean BMI 27.8 kg/m2 (SD 6.0) were analyzed. Sixteen (5.4%) of the tracts were above the 11th rib, 120 (40.8%) were above the 12th rib and 158 (53.7%) were infracostal. Multiple tracts were used in 16 (5%) of patients. There were no significant differences between patients undergoing supracostal versus infracostal puncture with respect to side, stone area, number of tracts, number of stones, or the presence of staghorn or struvite calculi, although there was a trend to larger stones and more staghorn calculi in the supracostal group. Success rates in the supracostal group (89.8%) were equivalent to the infracostal group (94.1%). Complication rates across groups were low, with no significant difference in complications between the supracostal and infracostal puncture groups, respectively, across Clavien grade I (12 vs. 1), grade II (4 vs. 11), grade IIIa (4 vs. 0), grade IIIb (2 vs. 0), and grade IVa (1 vs. 2), p = 0.067. All four (2.6%) Clavien grade IIIa complications in the supracostal group were pleural complications requiring chest drain insertion. No patients required a blood transfusion or angioembolisation.
When indicated, supracostal access can provide excellent outcomes, particularly for patients with complex stone disease while obviating the need for multiple tracts or retreatment. Although complications, particularly pleural, occur more frequently in those patients undergoing supracostal puncture, the incidence is low and acceptable considering the significant advantages in this patient population.
The purpose of this study was to describe the natural history of post-ureteroscopic renal stone fragments ≤4 mm based on computed tomography (CT) follow-up.
Patients treated with flexible ureteroscopy and holmium laser lithotripsy for renal urolithiasis from May, 2001 to April 2006 by a single surgeon (RBN) were retrospectively identified. Patients with residual renal fragments measuring ≤4 mm on initial postoperative CT and at least one additional follow-up CT were included. Main outcomes measured were stone event (emergency visit or stone procedure) and spontaneous fragment passage. Fragment growth and location were also recorded. Patients with ureteral residual fragments, fragments >4 mm, cystine stones, and those with anatomical anomalies were excluded.
Among 267 ureteroscopies, 134 were stone-free on the first postoperative CT (50.2% stone-free). Among the remaining 133 ureteroscopies, 50 met inclusion criteria. The mean fragment sizes at each follow-up CT were 2.6, 3.8, 5.2, and 2.4 mm at 3.9, 13.8, 24.9, and 38.7 months, respectively. Overall, the mean follow-up duration was 20.8 months (1.7 years). During this time, 10 ureteroscopic fragments (20%) passed spontaneously and 7 (14%) led to stone events. The remaining 33 (66%) retained asymptomatic residual fragments which remained relatively stable in size.
Approximately one-in-five post-ureteroscopic renal stone fragments ≤4 mm passed spontaneously within approximately 1.7 years of follow-up. One-in-seven fragments led to a stone event. The majority of residual fragments, however, remained asymptomatic and stable in size.
Percutaneous nephrolithotomy (PCNL) is the treatment of choice in patients with large stone burden or when other modalities of treatment are not successful. The stone-free rates after PCNL have ranged from 70 % to 85%. At the same time, the use of second look nephroscopy is assumed to increase stone-free rate. However, the predictors of having residual stones post PCNL have not been studied previously. Our objective is to evaluate the preoperative and perioperative factors associated with residual stones after PCNL. Our hypothesis is the use of second look nephroscopy is associated with improved outcome.
Data were extracted from an institutional review board-approved retrospective review of 230 procedures performed at our institution between January 2000 and December 2008. PCNL was performed by two endourologists with similar training and experience. Second look nephroscopy was done in patients who were not stone-free after the initial procedure. Outcome was defined as stone-free status after initial PCNL or second look nephroscopy while overall stone-free status is after subsequent additional procedures. Stone-free status was strictly defined based on complete absence of stones on subsequent radiological imaging. The assessed parameters were age, sex, Body Mass Index (BMI), stone size, number, and location, history of genitourinary anomaly or surgery, staghorn stones, prior surgery for the same stone, access location, and use of specific lithotripters. A sub-analysis was performed in patients with residual stones after the initial procedure to evaluate the role of second look nephroscopy. Univariate and multivariate analyses were performed using Pearson Chi-square, two-tailed t, and Fisher’s Exact tests. All variables were considered statistically significant at p < 0.05
Mean age and BMI were 54.15 years and 29.59 kg/m2 respectively. Univariate analysis revealed that stone diameter (p < 0.0001), complete staghorn stones (p < 0.001), and upper pole stones (p < 0.0001) were associated with having more residual stones while prior extracorporeal shockwave lithotripsy (p < 0.037) and holmium laser use (p < 0.01) were associated with improved stone-free status. In a sub-analysis of patients who had residual stones after the initial procedure, second look nephroscopy was associated with improved overall stone-free status (p < 0.019) in comparison to patients who did not have a second-look.
Preoperative and perioperative parameters can predict outcome of PCNL. Second look nephroscopy is associated with improved stone clearance. These results indicate that further studies with larger sample size are needed to construct preoperative prediction models.
|Stone location||N = 25||N = 24|
|Mean of largest diameter in mm (range)||10 (3–19)||9 (5–17)|
|Mean operative time (minutes)||59||51|
|Use of a basket|
|Remove stone fragments (p = 0.0123)||11||2|
|Ancillary procedures||SWL x 1, URS x 1||URS x 1|
|Stone free status at 3 months|
|Residual fragments <5 mm||2 / 20||4 / 23|
|Stone free||14 / 20||17 / 23|
|Success rate||80 %||91 %|
Initially introduced in the 1970s, ureteral access sheaths (UAS) were designed to improve ureteroscope entry and re-entry. Theoretically the increased irrigant outflow afforded by the UAS might allow the passive elimination of small stone fragments and thus improve stone free rates (SFR). This claim however has not been fully investigated and is only supported by retrospective evidence. We present the results of a multicentre prospective randomized trial to determine the impact of the use of UAS during ureteroscopic retrograde surgery (URS).
This trial was conducted at 4 Canadian centres. Patients with proximal and renal calculi, were randomized 1:1 to UAS (Navigator 11/13 Fr UAS) or no UAS. Ureteroscopy with Ho:YAG laser lithotripsy were performed according to each of the institutions standard protocols. The use of a basket was based on the surgeon’s discretion. Primary outcome was SFR at 3 months post URS. Secondary outcomes included operative time, complications and need for stent insertion.
Twenty-five patients were randomized to UAS and 24 to no UAS. Patient demographics were similar (age 55 vs. 52 years, gender 16 vs. 17 males, BMI 32 vs. 29). Stone characteristics were not significantly different (Table 1). We were unable to pass the sheath in 5 patients randomized to UAS and unable to access the stone in 2 in the no UAS group. One patient (no UAS) was lost to follow-up. No significant differences in primary or secondary outcomes between the two groups (Table 1) were found.
Our data shows that the use of UAS during flexible ureteroscopy was not associated with greater SFR. Furthermore, in this cohort the surgical time, need for ancillary procedures and stent placement were not affected. The use of UAS was significantly associated with increased use of a basket and therefore should be further explored since it may have an impact on the overall cost of the procedure.
Patients known to have previous nephrolithiasis are regularly followed in Stone Clinic with frequent imaging to rule out recurrences. Recently, there has been increasing awareness and concerns among both patients and health care professionals regarding long term risks from radiation exposure in follow-up of patients with benign disease. The aim of the present study was to quantify the yearly effective radiation doses associated with the follow-up of patients with nephrolithiasis in Stone Clinic at a single institution.
Retrospective chart review of 56 patients attending the Stone Clinic at a single academic centre between January and September 2009 was performed. Number and modality of diagnostic imaging studies in the previous 2 years were collected. Effective radiation exposure doses (reported in mSV) were calculated from the Dose Length Product values reported with each CT scan performed since November 2007. Radiation exposure from Kidney Ureter Bladder Plain Films (KUBs), Intravenous Pyelograms (IVPs) and fluoroscopic examinations were estimated from previous published data.
A total of 38 males and 18 females with a mean age of 49 years (range: 21–78 years) were included in this study. There were 137 KUBs, 9 IVPs, 47 fluoroscopic examinations and 73 CTs reviewed. Median yearly calculated effective radiation exposure dose was 36.87mSV (Mean: 33.86, range: 1.7 – 54.59 mSV) in 2008 and 21.64 mSV (mean 22.42, range: 1.4 – 77.27 mSV) in 2009. A total of 7 (12.5%) patients received a calculated effective radiation exposure dose >50 mSV per year. Mean effective radiation exposure dose was significantly higher in 2008 when compared to 2009, but did not correlate with stone location, age or sex of the patient.
Currently there are no guidelines on imaging modality or frequency in follow-up of patients with nephrolithiasis. A significant portion of patients are receiving effective radiation doses that exceed the current occupational radiation hazard limits. Therefore, urologists should be cognizant of the radiation exposure of patients when ordering imaging studies for follow-up of patients with benign disease.
Cardiac dysrhythmias (CD) may occur during extracorporeal shockwave lithotripsy (ESWL) of upper urinary tract stones and are rarely associated with serious side effects. The etiology and importance of avoidance of these CD remains unclear but the appearance of different patterns of multiple ventricular premature complexes (VPC) during ESWL is disconcerting and may lead to the need for intervention. We sought to identify variables influencing the likelihood of developing CD during ESWL which required ECG-gating as decided by the attending anaesthetist.
Sixteen cases were identified in a prospective fashion and their charts were compared with 56 control patients treated on the same day by the same anaesthetist and urologist for the variables shown in the tables. Patients with known CD or pacemakers were excluded.
All of the CD were described as frequent runs of bigeminy, trigeminy and/or multiple uni-/multifocal VPC which stopped promptly following ECG-gating. No other interventions were required and no side effects were noted.
|Continuous variable||Cases (mean ± SD)||Controls (mean ± SD)||Probability|
|Heart rate pre-Rx||72.6±14.5||77.9±14.9||0.16|
|Number of shocks||2327±572||2245±685||0.20|
|Class variable||Estimate||95% confidence limits||Probability|
|Sex F vs. M||0.848||0.237||3.026||0.64|
|Stent No vs. yes||1.075||0.235||4.925||0.27 Previous|
|ESWL No vs. yes||0.495||0.138||1.767||0.10|
|Side of Rx Left vs. right||0.011||0||0.201||0.005|
Worrisome CD developing during ESWL occur more frequently in younger patients and in those being treated for right sided stones. Heart rate pre-treatment, number and energy of shock waves, sex, presence of a ureteric stent and history of previous ESWL do not have an impact on the likelihood of them occurring. Normal rhythm can be established promptly by ECG-gating.
Laparoscopic (LP) and robot assisted pyelo-plasty (RP) are effective means of treating UPJ obstruction, yet analysis of these techniques is often limited to a single or few centres. We present preliminary results of the multi-institutional pyeloplasty study, comparing LP and RP.
Data was collected retrospectively from centres with experience in minimally invasive pyeloplasty. Preoperative data included demographic and anatomic data. Intraoperative data included pyeloplasty type, operative time, and complications. Postoperative data included complications, radiologic and symptomatic follow-up, and need for more procedures.
We have collected data from 486 patients, from 7 centres: 202 LP and 284 RP. LP was similar to RP in median age (35.0 yr, IQR = 21.0 yr vs. 36.0 yr, IQR = 27.0; p = 0.685). Median follow-ups for LP and RP were 12.1 mo (IQR = 14.5) and 9.0 mo (IQR = 16.0), p = 0.015. Preoperative pain was more frequent in LP than RP: 180 (90%) vs. 230 (81%), p = 0.016. Radiographically, both groups had similar median renal function (LP: 42.0%, IQR = 21.0; RP: 42.0%, IQR = 17.0, p = 0.214) and median T1/2 (LP: 26.0min, IQR = 18.0; RP = 30.0 min, IQR = 12.0, p = 0.325). The rate of previous UPJ procedure was similar for LP and RP: 13.4% v 9.8%, p = 0.193. Each had similar operative time (LP: 209.0 min (IQR = 108.3); RP: 196.0 min (IQR=104.0), p = 0.224). Intraoperative complications occurred in 3 LP and 6 RP (p =0.964). Postoperative complications occurred in 17/202 LP (4 urine leaks) and 17/284 RP (4 urine leaks), p = 0.257. Postoperative renal function (46.0%, IQR = 15.5 vs. 45.0%, IQR = 12.5; p = 0.102) and T1/2 (10.2 min, IQR = 8.3 vs. 10.0 min, IQR = 7.8, p = 0.153) were similar for LP and RP. Postoperative pain worsened or remained unchanged in 7% LP and 2% RP, p = 0.005. Postoperative obstruction worsened or remained the same in 9.5% LP and 2.8% RP, p = 0.007. Secondary procedures occurred in 16 (7.9%) LP and 6 (2.1%) RP, p = 0.002.
Comparison of LP and RP reveals excellent outcomes for both. Difference in postoperative pain may be due to a higher rate of preoperative pain in the LP group. Secondary procedures may reflect different practices that vary by institution. Overall, there was a slight advantage in outcome with RP.
The urinary and gastrointestinal tracts remain an enormous burden to the quality of life in the patient with a spinal dysraphism. We believe that the analysis of contemporary outcomes is essential for patient and family counseling.
After ethics approval, a chart review was performed to compile all pertinent genitourinary and gastrointestinal outcomes from the pediatric and adolescent spina bifida clinics at the Glenrose Rehabilitation Hospital in Edmonton, Canada. There were 152 patients under the age of 17 years with a spinal dysraphism identified.
The most common spinal cord pathology is myelomeningocele (45%), followed by tethered spinal cord (21%), lipomyelomeningocele (18%), spinal cord injury (8%), meningocele (1%) and other (9%). The most common level of myelomeningocele is lumbosacral (37%), followed by lumbar (31%), sacral (16%), thoracolumbar (10%) and thoracic (6%). 84% of children with a myelomeningocele have a ventricular shunt. Of our cohort, 46% perform clean intermittent catheterization, 40% are on an anticholinergic medication, and 46% void spontaneously. Six percent have used overnight catheter drainage and 3% have had either Botox injections or urethral dilation; 7% have an incontinent urinary diversion; 84% catheterize per urethra, and 16% via an abdominal stoma. Intestinocystoplasty rates varied with level of lesion, with 31% of thoracic myelomeningoceles, 22% of lumbar, 11% sacral, and 6% of tethered cord patients requiring surgical intervention. Of the entire population, 44% of patients above the age of 5 years are continent of urine. Of voiding patients, 40%, and 27% of those managed medically, are continent. Continence varies with level of lesion; with 33% of thoracic myelomeningocele patients continent, 27% lumbar 43% sacral, and 58% of tethered cords. There are 73% of patients who are continent of feces, 71% of those who manage their bowels conservatively are continent while 67% of those who have had advanced management (cecostomy or MACE) are continent. Twenty-four percent of patients have a history of hydronephrosis, and of these only 10% have persisted; 3% have mild renal insufficiency and 9% have documented renal scarring. None have required renal replacement therapy.
To our knowledge, this is the largest and most comprehensive cohort reported in the literature. This data will help serve as a reference for a contemporary spina bifida clinic, lead to a prospective study, and help improve pre and post-natal counseling.
Attention to the management of pediatric high-grade renal injuries has been limited. Current management of high-grade pediatric renal injuries has followed algorithms studied and designed for adult patients. Our aim was to describe initial and subsequent management as well as eventual outcome of high-grade pediatric renal injuries using a national data set.
High-grade renal injuries are uncommon preventing single-institution analysis; therefore, we utilized the National Trauma Data Bank (NTDB) 2002–07, the largest current collection of trauma registry data of injured persons. Pediatric (ages 0–18) renal injuries were identified by AIS codes and converted to American Association for the Surgery of Trauma (AAST) injury grade. We analyzed demographic data, injury severity score (ISS), and acute management of AAST grade IV and V injuries. Interventions were stratified by endoscopic, endovascular, and open operative procedures.
|Non-operative n = 274 (60%)||Endoscopic n = 32 (7.0%)||Endovascular 22 (4.8%)||Open operation n = 132 (29%) Grade n (%)|
|232 (85)||27 (84)||16 (73)||79 (60)||V|
|42 (15)||5 (16)||6 (17)||53 (40)||Mean ISS|
|(SD)||25 (14)||17 (7.1)||34 (15)||29 (13)|
|Median hours to Procedure||-||42||<1||1|
|Number of additional procedures|
|Total no. patients with additional procedures||-||19||1||15|
|Total no. additional procedures||30||1||27|
We identified 2213 pediatric renal injuries, including 460 (21%) high-grade injuries (354 grade IV and 106 grade V). Of these, 68/460 (14.7%) were penetrating. Initial management for each cohort is shown in the table. Successive procedures were more commonly needed for the endoscopic and open surgical cohorts. Among the operative cohort needing successive surgery, 4/15 had eventual nephrectomy. The most common successive procedure among the endoscopic cohort was retrograde pyelography. Endovascular management appeared durable as only one required successive therapy. Among the 460 patients, overall renal salvage was 77.2%. Nephrectomy was only performed in the open operative cohort, with a renal salvage rate of 20.5%. Comparison of mean ISS between open operative patients with and without renal salvage was 30.9 and 31.5 respectively.
Non-operative management of grade IV and V renal injuries is common in children. Given that ISS is similar in the non-operative and open operative groups, it is unclear what factors led to surgical intervention. This argues in favor of a more informative grading system, perhaps based not only on anatomic injury, to guide management decisions.
Bladder reconstruction performed by enterocystoplasty or bioengineered substitutes is associated with significant complications, which led us to elaborate a vesical equivalent (VE) as a new alternative. This model has already proven its structural conformity. The challenge is to reconstruct our model in a physiological environment, with the use of a bioreactor that mimics the dynamic of bladder filling and emptying, to acquire watertight properties and increase mechanical resistance. It is also necessary to develop a microvascularization within our reconstructed tissue, in order to deliver oxygen and nutrients for its survival after grafting.
Three cellular types are extracted simultaneously from a small porcine bladder biopsy, according to a technique previously described. Fibroblasts, urothelial and endothelial cells evolve in a three-dimensional culture to obtain a VE easy to handle. It is dynamically cultured in our bioreactor, which delivers cyclic pressure progressively increasing up to 15 cmH2O every four hours, followed by a rapid decrease. The VE are characterized by histology, immunohistochemistry and electron microscopy. In addition, mechanical resistance is evaluated by uniaxial tensile tests, and the tissue absorption is measured with 14C-urea, which quantifies the degree of impermeability of our VE.
Compared to our model in static conditions, the dynamic culture led to the obtention of a thicker matrix, with a pseudostratified urothelium on a more defined basal membrane. Moreover, positive markers for cytokeratin 20 and the physiological aspect in electron microscopy demonstrated the terminal differentiation of our VE. Permeability profiles displayed the same profile as the native bladder, coinciding with uroplakins organization into apical plaque. Finally, the mechanical results obtained showed an appropriate resistance for suturing and handling, and this, even when a network formed by capillary-like structures were observed throughout the matrix.
This method to produce VE seems very promising to meet the needs in the urological field. Our substitute has proven its efficiency as a barrier to urea and has a sufficient mechanical resistance to support physiological pressures. Additionally, this model is completely free of exogenous biomaterials, and its endothelialization could promote the early vascularization process after grafting and it would significantly reduce inflammation and possible rejection.
Macroplastique® gained acceptance in many parts of the world as an injectable bulking agent for correction of vesico-ureteral reflux or incontinence. As with other substances, the long-term consequences of such intervention remain largely unknown. Herein we present one important complication detected during follow-up in a single institution series.
A total of 232 children underwent subureteric injection between 1998 and 2004, being regularly monitored since. Of these, all patients that have presented with submucosal stones in the prior area of injection have been prospectively captured. Clinical features and data on patient characteristics were obtained by chart review.
Three patients ages 10, 13 and 15 developed enlarging submucosal bladder calcifications 5, 7 and 9 years following the initial injection for vesicoureteral reflux. In all the intervention was uneventful and no clinical or sonographic abnormalities were detected after the procedure. Patients subsequently presented with worsening hydronephrosis, hematuria and irritative lower urinary tract symptoms. On ultrasound and pelvis X-ray we encountered calcifications at the site of prior injection. At time of endoscopic surgery the calcified material was extracted after unroofing the overlying eroded mucosa. To date no recurrences have been detected and none of the patients have undergone ureteral reimplantation.
This experience calls attention to a potentially important complication that can be encountered following endoscopic injection with Macroplastique®. Monitoring of these patients appears warranted as long-term issues with new injectable materials remains largely unknown.
Although staged buccal mucosa graft (SBMG) is a well accepted technique for salvage urethroplasty there are few reports describing pitfalls and outcomes of this technique for redo hypospadias repair in children.
The charts of patients who underwent substitution buccal mucosa graft urethroplasty performed for urethral plates not amenable to repeat single stage reconstruction were reviewed. During the first stage the diseased urethra was removed and a quilted de-fattened buccal graft placed over a well vascularised bed. The second stage graft tubularization was performed approximately 6 months later. A second covering layer was used in all cases. Age, quality of the graft immediately before tubularization, meatal position presence of Balanitis Xerotica Obliterans (BXO) and complications were recorded.
Thirty patients underwent 32 repairs over a 5-year period. Mean of age at the first stage was 7 years (range 1–17) and mean interval between stages was 9.3 (range 5–13) months. Mean follow up after the second stage was 19.5 months (range 4–44). Meatal position before first stage was proximal in 44%, midshaft in 39% and distal in 16%. The buccal graft was harvested from the cheek in 25, the lower lip in 2 and from both sites in 4 cases. Nine patients had proven BXO. There were no donor site complications. In 16 cases the graft developed variable degrees of fibrosis/retraction and/or induration. In 4 of these the fibrosis was severe enough to warrant re-grafting. Complications after the second stage procedure occurred 11/32 repairs (34%): Urethral stenosis, glandular dehiscence and urethro-cutaneous fistula occurred in 5, 3 and 3 repairs, respectively. Complications occurred in 9 (81%) of the 11 patients with some degree of graft fibrosis or induration at second stage whereas only 4(19%) complications occurred in 21 patients without this unfavourable graft finding (p < 0.001). Age, presence of BXO and meatal position were not significant factors associated with adverse outcomes.
Staged buccal mucosa urethroplasty is a suitable technique for salvage urethroplasty. Donor site complications are rare. Complications were seen in approximately one third of the patients, occurring mainly in fibrotic and indurated grafts which, in retrospect, should not have been tubularized.
Ureteropelvic junction obstruction (UPJO) is a common renal anomaly diagnosed on antenatal ultrasounds and does not always cause impairment in renal function. Children with UPJO can be managed with surgery or observed with follow-up imaging. Surgery carries risks of anaesthetic complications, bleeding, infection, and reoperation while observation may result in a decline in renal function. Because both interventions may pose certain risks, it is imperative to determine which has the best outcome with lowest risk. We conducted a systematic review to analyze the evidence for surgery versus observation in children with UPJO to determine what impact the interventions have on renal function.
The Cochrane Controlled Trials Register, MEDLINE, EMBASE, PubMed, Web of Science, Scopus, and OCLC Proceedings First Database were searched. Identified studies included children antenatally diagnosed with UPJO who underwent observation or surgery for this condition. Patients had to have had a nuclear renal scan postnatally demonstrating preserved (>40%) differential function. Secondary outcomes including infection, hydronephrosis, drainage, pain, and hypertension were also reviewed.
Twenty-one studies were selected for review. One RCT, one single arm cohort for surgery, and 19 single arm cohort studies on observation were found. The proportion of patients with decline in renal function during observation ranged from 2–73% and was 7% in the single surgery study. Combining all studies 13% of patients in the observation group had deterioration in renal function, requiring surgical correction and 26% of those patients had a documented return to baseline differential renal function. Other indications for surgery in the observation group included urinary tract infections in 5 studies (9%), pain in 4 studies (7%), and worsening hydronephrosis in 2 studies (23%). The only surgical complications were loss of renal function in the surgery study.
The most appropriate management of children with antenatally diagnosed UPJO and preserved differential renal function is unclear. Several cohort studies on observation exist showing maintained normal renal function. Children may present later with infection or pain requiring surgical correction. Surgery can also result in a decrease in renal function but in general has a low incidence of complications. Further prospective studies are necessary to draw a definitive conclusion and should include quality of life data.
The natural history of multicystic dysplastic kidney (MCDK) is generally accepted to be benign. By definition, MCDK shows 0% relative function (fnx) on renal scintigraphy. However, given the lack of fnx and dysplastic characteristics of MCDK, it remains controversial whether kidneys with very low relative fnx (close to 0%) also follow the same benign natural history and merit the same expectant management as MDCK. We determined whether very low functioning kidneys have a unique clinical course, a distinct clinical and pathological outcome, and prompted different management history compared with MCDK.
We reviewed all DMSA scans performed in our institution from 2000 to 2008 and selected those possessing one renal unit with 0%–10% fnx and ultrasonographic (U/S) features of MCDK. For purposes of the study, scans were divided into an MCDK Group (0% fnx) and a Dysplastic/Dysmorphic (DK) Group (1 to 9% fnx). Records from patients in each group were then compared with respect to natural history of the index kidney, clinical course, and management history, with emphasis on possible related complications: hypertension, vesicoureteral reflux, pyelonephritis, and carcinoma.
A total of 162 patients had a DMSA with one renal unit with <10% fnx and U/S features of MCDK. As defined, 120 patients fit the MCDK Group criteria and 42 patients fit the DK Group criteria. Many pts in the DK Group were labeled as “MCDK” in their records. There were 16/120 (13%) in the MCDK Group (0% fnx) who experienced recurrent UTI or hypertension, for which 7 (6%) underwent nephrectomy (Nx). In the DK Group of patients with minimal fnx, 13/42 (31%; p < 0.5 vs. MCDK Grp) showed complications (UTI, hypertension, carcinoma). Seven of them (17%) underwent Nx for size increase or hypertension (p <0.01 Nx vs. MCDK Group). One DK patient, (1/42 vs. 0/120 MDCK Group; p <0.01), a 14yr female followed for several years by U/S developed progressive enlargement of the index kidney. Imaging was suspicious and Nx confirmed renal cell carcinoma. This patient currently shows no evidence of recurrence at 5 yrs F/U.
U/S characterization of MCDK should be supported by a DMSA scan confirming true 0% fnx before diagnosis of MDCK is used clinically. Conversely, renal units with residual fnx (1 to 9%) may be at risk for more and potentially lethal complications. The non-0% low functioning kidney seems to progress differently compared to those with true 0% fnx, thus advocating for closer clinical scrutiny and a lower intervention threshold in the non-0% kidney.
Brachytherapy has been shown to have equivalent biochemical free and cancer specific survival to other treatment modalities including external beam radiotherapy (EBRT) and surgery for low risk patients. However, intermediate risk patients have historically not been offered brachytherapy as primary treatment. Given the ability to achieve extremely high dose rates that are not locally possible with EBRT, we hypothesize that brachytherapy may be equivalent to EBRT for treatment of intermediate risk prostate cancer. We have adopted its use as monotherapy for this risk group, and evaluated the biochemical control, along with the acute and delayed morbidity post treatment.
A retrospective review of patients treated with brachytherapy between June 2003 and Dec 2008 at the Manitoba Prostate Centre was conducted. Ninety-five patients were treated with brachytherapy alone for intermediate risk disease (T2b or T2c, Gleason score 3+4 = 7 or 4+3 = 7, PSA ≥10 but <20). Only patients with at least 3 post-treatment PSA measurements (n = 57) were assessed for biochemical failure (mean follow-up period 13.75 months, range 8 to 53 months). Biochemical (PSA) failure was defined using the Phoenix, or Nadir+2 definition and secondarily, the traditional American Society for Therapeutic Radiology and Oncology (ASTRO) definition of 3 consecutive rises over nadir. We also evaluated acute and late morbidities including urinary and bowel symptoms, and erectile dysfunction in all 95 patients.
Of the 95 patients evaluated, no adjuvant treatment was given for biochemical control. In the 57 patients assessed for biochemical failure, PSA nadir ranged between 0.01 to 2.86; mean time to nadir = 22 months (range 2–57 months). Biochemical failure occurred in 1 patient (Phoenix) and in 2 patients (ASTRO). Within the entire study population (n = 95), 18 patients (19% ± 8%, 0.95 CI) had urinary retention > 2 weeks requiring catheterization; 4 patients (4.2% ± 4%, 0.95 CI) developed erectile dysfunction post treatment and 2 patients reported some degree of urinary incontinence.
Our results suggest that biochemical control can be achieved with brachytherapy alone for intermediate risk localized prostate cancer, with an acceptable rate of treatment related morbidity. Brachytherapy might be an alternative standard of care treatment for localized, intermediate risk prostate cancer.
Whether men on active surveillance (AS) for low volume, low-risk prostate cancer (CaP) can be effectively managed with focal therapy has yet to be determined. Transrectal ultrasound-guided biopsy (TRUS-BX) combined with other staging modalities are important parameters in deciding who may be a candidate for focal therapy (FT). Our aim was to investigate initial positive and repeat TRUS-BX findings in men on AS to determine how often and to what extent an altered disease profile occurred on second biopsy; the rationale being that this information may be important in managing candidates for FT.
Our institution prospectively maintains a TRUS-BX database, with 3 radiologists performing all biopsies (>2000 systematic biopsies/year). Our AS cohort typically have low grade, low volume disease (≤3 cores positive, less than 40% of any core positive, gleason ≤7) and are candidates for definitive therapy. Of those with CaP in a focal area of the prostate (1 side) on first biopsy, we determined whether CaP was evident in a second biopsy and whether it was identified in a new location such as the opposite side of the prostate. The difference in grade and percentage of cores positive for cancer between the first and second biopsy was also determined.
A sample of our AS cohort with CaP included 152 men who had 2 biopsies read by the same uropathologists. The mean age was 65 and the mean time between biopsies was 18 months with an average PSA increase from 5.71 to 6.6 (p = 0.0003). For positive cores, the mean % of cancer in individual cores was 8 on first biopsy and 9 on second biopsy (p = NS). The number of cores positive on first biopsy was 18% of all cores taken and on second biopsy was 13% (p < 0.0001). The Gleason score increased in 25 men (16%), stayed the same in 77 men (50%) and decreased or was undetectable in 53 men (34%) (p < 0.0001). On second biopsy, 51 men (33%) had no detectable cancer. When CaP was positive unilaterally on the first biopsy (n = 134), 13 patients (8.5%) had cancer detectable on the contralateral side only on second biopsy. Of those with unilateral cancer on initial biopsy 22 (14.5%) had cancer evident on both sides on second biopsy.
CaP was present on the contralateral side in 23% of repeat biopsies suggesting this should be performed prior to considering FT in men on AS.
Minimally-invasive treatments for localized prostate cancer, that offer good local control over disease with a low side-effect profile, would have a major impact in improving the management of this disease. MRI-guided transurethral ultrasound therapy is a candidate technology in which planar high-intensity ultrasound energy is delivered to the prostate gland, via a transurethrally inserted device to generate a precise region of thermal coagulation. Previous studies in gels and canines have demonstrated the feasibility of using active MR temperature feedback to control spatial heating to a specified target region. This phase I study was designed to evaluate the safety and feasibility of this technique in humans.
MRI-guided transurethral ultrasound therapy was administered to a pre-determined region of the prostate of men diagnosed with localized prostate cancer (pT1c-pT2a). Subjects immediately underwent radical prostatectomy post-procedure, and the pattern of thermal damage measured on histology was compared with imaging predictions. The procedure utilized a 1.5T closed bore MRI and each subject received a combination of sedation and spinal anaesthesia to eliminate pelvic sensation and reduce motion. High-intensity ultrasound energy was delivered to a 180° sector in the prostate and spatial temperature maps were obtained every five seconds using the PRF shift technique. The temperature measured at the boundary of the target region during treatment was used by the treatment system to adjust the power and rotation rate.
Five patients, median age 59 (range 49–69), have been successfully treated to date. Baseline biopsy gleason scores were 3+3 (n = 1) and 3+4 (n = 4) and the median pre-biopsy PSA, 4.5 (range 2.7–5.3). The transurethral device was inserted without difficulty into patients in the supine imaging position. Spinal anaesthesia and sedation effectively eliminated patient discomfort and motion during the 2 hour procedure. Precise positioning of the transducer within the prostate was achieved under image guidance, and successful device rotation was achieved within the prostate. MR temperature measurements within the prostate were achieved with a spatial resolution of 2 mm (in-plane) and a temperature uncertainty of 1°C every 5 seconds, using a conventional pelvic surface coil array. Temperature measurements were stable, and not affected by motion or breathing. A continuous pattern of heating was delivered over the target region, and the targeting accuracy was 1.0+/−1.5mm. There were no reported complications.
MRI-guided transurethral ultrasound therapy is safe and capable of generating a precise region of thermal damage within the prostate gland under active MR temperature feedback.
The effect of obesity has been established to dilute PSA concentrations and affect how PSA is interpreted. The clinical application of this effect remains unclear. We determined how obesity measured by Body Mass Index (BMI) could affect the significance of PSA levels among men undergoing prostate biopsy in a PSA screening program.
We conducted a case-control analysis among 786 men with a PSA level of <20 ng/mL who underwent a prostate biopsy using the probability of prostate cancer of greater than 25% using a Prostate Cancer Risk Calculator (www.prostaterisk.ca). We compared BMI measurements between prostate cancer cases and controls. We examined for confounding and effect modification to determine the effects of BMI on PSA in evaluating prostate cancer risk using multivariate logistic regression analysis.
Among the 786 men, 203 (25.8%) were diagnosed with prostate cancer, consistent with the Prostate Cancer Risk Calculator prediction. PSA level did not predict the presence of prostate cancer. The median PSA level among cases (6.1 ng/mL) were not significantly higher than controls (5.8 ng/mL, p = 0.11). Similarly, the distribution of BMI among cases (median=26.4) and controls (median=26.7) were not significantly different (p = 0.85). However, when we stratified by obesity (BMI index ≤30 vs. >30), PSA levels were significantly higher among cases (median=6.1 ng/mL) than controls (median=5.7 ng/mL, p = 0.05). PSA was not significantly different between cases and controls among men with BMI >30. When we examined for confounding within a multivariate logistic model (including age, ethnicity, family history of prostate cancer, and DRE), both BMI and PSA were not significant predictors for prostate cancer. When the analysis was stratified by BMI index, the adjusted odds ratio for prostate cancer by PSA category was 1.7 (95% CI: 1.2–2.3, p = 0.001) for men with a BMI of ≤30. The adjusted odds ratio for prostate cancer by PSA category for men with a BMI >30 was 1.2 (95% CI: 0.7–2.2, p = 0.44).
Obesity measured by BMI appears to affect PSA as a risk modifier towards prostate cancer risk. The significance of PSA levels should be factored accordingly using BMI Index.
Genome-wide association studies (GWAS) for prostate cancer have found extensive single nucleotide polymorphisms (SNPs) assoicated with prostate cancer. However, none have been found to be associated with aggressive forms of prostate cancer.
We conducted a GWAS among men who had a prostate biopsy, using a two-stage approach. In the first stage, 316 cases and 229 controls were genotyped using the Affymetrix 500K SNP array (443,816 SNPs). Cases were patients with aggressive forms of prostate cancer using the established D’Amico classification criteria, and controls were biopsy proven normal patients. In the second stage, we genotyped positive SNPs found from stage 1 among 3439 patients who underwent prostate biopsy for prostate cancer screening. We investigated their clinical significance by examining their association with D’Amico criteria outcomes and by nomogram analysis in predicting prostate risk.
We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p-values for association 1.3x10−10−3.2x10−11) and 15q21 (rs4775302 and rs1994198, p-values for association 3.1x10−8−8.2x10−9) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8 to 3.0, p-value 0.003 to 0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk.
We identified significant associations at 10q26 and 15q21 with aggressive forms of prostate cancer. Nomogram analysis shows potential clinical applications of these SNPs in prostate cancer individual risk assessment.
Inecalcitol is a novel synthetic vitamin D3 analogue with potent antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol in animal models.
In this study, escalating dosages of inecalcitol was combined to chemotherapy in naive HRPC pts. Safety and efficacy were evaluated in groups of 3–6 patients receiving inecalcitol daily or every other day on a 21-day cycle in combination with docetaxel (75 mg/m2 q3w) and oral prednisone (5 mg bid). Biphosphonates were prohibited during the first cycle. Patients received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Calcemia, creatininemia and CBC were assessed weekly; biochemistry, ECG and PSA every 3 weeks. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months.
Seven dose levels, from 40 to 2000 μg have been evaluated in 47 pts; 42 have completed the study (14 bone metastases; 5 extrasqueletic metastasis, 21 bone and extrasqueletic metastases; 2 PSA-only disease) of which 33 pts have completed 6 cycles and 5 pts are still being treated at 2000 μg. Median age was 71 years [range, 53–87], median Gleason score (Gs) 7 [42% Gs 10–8, 58% Gs 7–6] and median PSA 41.5 ng/mL [range, 0.9–962.4]. No significant changes in calcemia were observed. Eleven pts showed a hypercalcemia G1 of short duration and just above the upper limit of normal value. No hypercalcemia G2 was observed. Most adverse events (AE) were G1-2, asthenia (19 pts), constipation (14 pts), diarrhea (13 pts). G3-4 AEs were neutropenia (11 pts) lymphopenia (9 pts), asthenia (3 pts), general health deterioration (2 pts) and diarrhea (1 pt). None of these AEs was considered related to inecalcitol. Of the 38/42 evaluable pts for PSA response, 33 (87%) had ≥30% PSA decline.
Results from this ongoing study show the safe toxicity profile of inecalcitol when given daily in HRPC pts even at mg level. PSA responses with this combination are encouraging. As DLT was not reached, higher dose of inecalcitol (4000 μg/day) are being tested.
Our previous study on prostate cancer (PCa) tissues shows that the alternative NF-kB proteins RelB and p52 localize to the nucleus more frequently than classical NF-kB proteins RelA and p50. We also reported on a small cohort that the nuclear localization of RelB correlates with increasing Gleason scores. The present study attempts to confirm this observation in a larger cohort and determine if this pathway may be implicated in the stage progression of prostate cancer.
To evaluate RelB expression and cellular localization, archival formalin-fixed, paraffin-embedded prostate specimens were used to construct a first tissue microarray (TMA) containing non-malignant tissue adjacent to the tumour (n = 55), prostatic intraepithelial neoplasia (PIN) (n = 31) and hormonosensitive (HS) PCa samples (n = 63). A second TMA was also built including hormonorefractory (HR) tumour specimens (n=36). Statistical analyses were used to evaluate the correlations between RelB and clinical and pathologic disease progression.
Our immunohistochemical analysis showed a differential expression between non-malignant and tumour tissues. Indeed, RelB was largely expressed in the cell cytoplasm of tumours, including HS (87,3%) and HR (91,7%) samples compared to non-malignant tissue adjacent to the tumour (49,1%; p < 0,001) and PIN (48,4%; p < 0,001). Moreover, RelB was more frequently localized in the nucleus of HR PCa (97,2%) than in HS (63,5%; p < 0,001), non-malignant tissue adjacent to the tumour (51%; p < 0,001) and PIN (48,4%; p < 0,001).
RelB is over-expressed in PCa tissues with a frequent nuclear localization that increases with PCa stage progression. This extremely high nuclear expression in HR PCa tissues suggests that activation of the alternative NF-kB pathway may be implicated in the PCa progression from HS to HR status. Ongoing studies including the other alternative NF-kB p52 will hopefully shed light on the role of both NF-kB pathways in prostate cancer progression, its use as a potential prognostic marker as well as a possible therapeutic target for the future.
Overexpression of pro-inflammatory cytokines has been associated with prostate cancer (PCa) progression and hormone-refractory (HR) status. Previous work has shown that IKK plays a part in chronic inflammatory states, such as the rheumatoid arthritis. We have previously reported differences in IKK expression between hormone-sensitive (HS) and HR cell lines. HR cells express significantly higher levels of IKK than HS cells. In addition, IKK modulation (knockdown or overex-pression) correlates with IL-6 secretion in HS and HR cell lines. Since IL-6 and IL-8 are associated with PCa progression, we formulated the hypothesis that IKK may be implicated in the progression of HS to HR status.
To validate this hypothesis, we performed IKK staining on paraffin-embedded prostate tissue microarrays containing cores from normal tissues (n = 47), non-malignant tissues adjacent to the tumour (n = 53), prostatic intraepithelial neoplasia (PIN) (n = 28), HS tumours (n = 62) and TURP samples from HR patients (n = 31). We also evaluated if the IKK expression was predictive of eventual clinical outcome.
We found a clear correlation between the cytoplasmic levels of IKK expression in PCa and cancer progression. We observed a low cytoplasmic IKK expression in normal, PIN, and non-malignant tissues adjacent to the tumour, for which no difference in IKK levels was found. HS tumours presented a significant increase of cytoplasmic IKK expression compared to normal tissue, PIN and non-malignant tissues adjacent to the tumour (p ≤ 0,005). Moreover, we observed the highest cytoplasmic IKK expression in HR tissue (p = 0,005). Finally, we studied the link between cytoplasmic IKK expression levels and clinical outcome. In a subset of patients where tissue from the same patient at diagnosis and at the time of HR status was available IKK expression was predictive of progression to metastases and HR status (Pearson correlation = 0,340; p = 0,007). We however found no correlation between nuclear IKK level and pathologic status or cancer progression.
Our results suggest that IKK is involved in PCa stage progression and may be implicated in the progression from HS to HR status. These findings justify further studies to elucidate the exact mechanisms surrounding IKKe in PCa progression.
Patients with high prostatic specific antigen (PSA) levels have often been recommended treatment with either radiation therapy or androgen deprivation because of the high risk of metastasis. We reviewed our experience in patients with a preoperative serum PSA ≥20 ng/mL treated with radical prostatectomy (RP). Our objective was to describe disease recurrence and mortality patterns.
Between 1988 and 2007, 261 patients with a median (range) age of 63,2 (45 to 81) years with a preoperative PSA ≥20 ng/mL, underwent RP in our institution. All patients had a negative preoperative bone scan and negative additional radiological testing as needed. Charts were comprehensively reviewed. The Kaplan-Meier method was used to analyze the disease-free survival for PSA and clinical recurrence.
Median (range) PSA was 29.4 (20–1000 ng/mL): 137 (52,5%) had a PSA level between 20 and 30 ng/mL while 81 (31%) of patients had a PSA level ≥40 ng/mL. At final pathology, the disease was organ confined in 89 (34%), extra capsular extension was found in 158 (60%), seminal vesicle invasion in 100 (38%), lymph node involvement in 84 (32%) and positive surgical margins in 163 (62%). Eighty-nine patients received neoadjuvant androgen deprivation therapy (ADT), 152 had ADT with or without radiation therapy after RP, 29 had adjuvant radiation therapy and 76 had salvage radiation therapy. With a median follow-up of 7.75 years, 20/59 patients died from prostate cancer while 33 died from other causes (6 patients with cause of death unknown) and 159 patients had biochemical recurrence, of which 28 developed bone metastasis. One hundred and two patients remained biochemical free at a mean follow-up of 8.9 years. The actuarial recurrence-free survival at 5 and 10 years was of 45.7% and 34.8% respectively.
Even alone, radical prostatectomy performed in a high-volume institution may provide cure in up to a third of patients with very elevated PSA (>20 ng/mL). Despite a high rate of recurrence in this aggressive form of disease, about only a third of deaths are caused by prostate cancer which highlights the importance of postoperative adjuvant therapies.
ADT is used in up to 1 in 2 men with prostate cancer. Osteoporosis and fragility fractures are important side effects of ADT. Guidelines recommend 2 important bone health practices for men on ADT – measurement of bone mineral density with dual x-ray absorptiometry (DEXA) and use of bisphosphonates in men at risk of osteoporosis. The implementation of these guidelines in routine practice is not well known.
Using linked administrative databases, we identified 25,802 men (mean age 75.9 y, range 66–100 y) with prostate cancer who were treated with at least 6 months of ADT (82.7%) or who underwent bilateral orchiectomy (17.3%) in Ontario, Canada between 1995 and 2005. Performance of DEXA and prescription of bisphosphonates were captured using specific procedure codes and drug identification numbers, respectively. Prior use of DEXA and bisphosphonates, as well as prior diagnoses of osteoporosis and fragility fracture, were captured with specific diagnostic codes and a 3-year look-back period. Annual rates per 100 person-years were determined for both outcomes.
Among 25,802 men, 3.09% had a DEXA more than one year prior to starting ADT, 3.14% had a prior diagnosis of osteoporosis, and 1.89% were using a bisphosphonate prior to ADT initiation. The rate of undergoing DEXA within 2 years of starting ADT rose from 0.50 per 100 person-years in 1995 to 19.47 in 2005. Rates of DEXA testing were somewhat higher among those with a prior diagnosis of osteoporosis, prior DEXA test, or prior fragility fracture but did not reach rates above 50 per 100 person-years in any of these groups. Bisphosphonate use increased from 0.27 per 100 person-years in 1995 to 3.18 in 2005 among prior non-users. More men on ADT were started on a bisphosphonate in the third year after starting ADT as compared to the second year, and rates were higher in year 2 than year 1. Less than one-third of men starting a bisphosphonate underwent any DEXA testing within 12 months of bisphosphonate initiation.
Rates of DEXA testing and bisphosphonate use have increased over time among older men starting ADT, but significant gaps and delays remain in the quality of bone health care in this population.
Several risk stratification schemes are available for the prediction of the need for extended pelvic lymph adenectomy (ePLAD) in patients with prostate cancer undergoing radical prostatectomy (RP). None of those tools rely on pathological diagnosis. We examined the relationship between ECE and side specific and overall rate of LNI and ePLND.
Between 1996 and 2008, 4806 patients underwent a RP with an ePLAD at a single European institution. Clinical and pathological information was available for 4790 men. Analyses were performed using the entire dataset as well as in a side specific fashion, where each lobe of the prostate and ipsilateral lymph node invasion was considered without accounting for contra lateral finding.
Overall, 7.9% of all patients undergoing LND had lymph node invasion (LNI). The rate of LNI was 0.8% in absence of ECE vs. 5.7% and 15.1% when respectively side specific ECE or bilateral ECE was recorded. The rate of concordance (75.5%) between side specific ECE and side of LNI was statistically significant (p < 0.001) and independent predictor status of ECE, (none vs. side specific (OR: 5.66; p < 0.001) and none vs. bilateral (OR: 10.97; p < 0.001) was confirmed in multivariable models including PSA, biopsy Gleason sum and clinical stage.
Single sided ECE might indicate the predominant localization of the main tumour within the prostate. Our data demonstrated a relationship between ECE and the risk of ipsilateral LNI. These findings should be considered in future studies, including assessment of preoperative side specific tumour characteristics and side specific index tumour volume for testing the ability of developing side specific LNI prediction tools. These prediction tools could enable the surgeon to better decide if in such patients, a side specific extended or pelvic LND is required.
Surgical wait times have become a contentious quality indicator in universal health care systems. The potential for cannibalization towards higher priority surgical cases has led to concerns for the inevitable prolonged wait times for non-priority urologic procedures. We describe and evaluate the effect of surgical wait times on the early outcomes and perioperative complications after transurethral resection of the prostate (TURP).
Patients undergoing TURP for benign disease at a single centre in 2008 were included in this study. Wait times were determined utilizing a prospectively collected administrative database reporting a summary wait time from the time of OR booking to completion of surgery. Clinical data was supplemented by extensive chart review and included patient characteristics such as age, comorbidity (ASA score) and indication for surgery. Associated outcomes investigated included additional hospitalization or urgent care visits while on the wait list, successful postoperative trial of voiding and complications within three months of surgery.
Eighty-four patients with a mean age of 73 were identified having a TURP for benign disease and 46% of patients presented with urinary retention. Mean surgical wait time for the cohort was 59 +/− 48 days and there was no significant association with wait times and age or ASA score (Spearman correlation, 0.200, p = 0.07, 0.066, p = 0.547 respectively). There did not appear to be significant triaging of patients based on a presentation of urinary retention. Additional hospital visits for urologic complications was associated with prolonged wait times for TURP (p = 0.03, t-test); however, lower wait times for TURP was significantly associated with early failures of voiding and early postoperative complications (p = 0.02, p = 0.03 respectively; t-test). Dichotomizing wait time data at the median of 48 days confirmed that longer waits for TURP lead decreased postoperative complications (p = 0.033; chi square), including early failures of spontaneous voiding (p = 0.005; chi square) but was led to increased health care visits while waiting for surgery (p = 0.038; chi square). Subset analysis demonstrated that these results appeared to be driven mostly by those with a presentation of urinary retention.
Prolonged wait times for urologic surgery are distressing for patients and can be a quality indicator of health care delivery. This retrospective study suggests that modest delays to TURP did not negatively affect early outcomes and, in fact, shorter wait times were associated with higher postoperative complications. However, these findings need to be balanced with higher likelihood of complications and resource utilization during the prolonged waits for surgery.
We evaluated our initial experience with the GreenLight HPS laser, a technologically improved version of the potassium-titanyl-phosphate (KTP) laser for PVP.
Transurethral PVP was performed using a GreenLight HPS side-firing laser system. Patients had American Urological Association Symptom Score (AUASS), Quality of Life (QoL) score, Sexual Health Inventory for Men (SHIM) score, serum prostate-specific antigen (PSA), maximum flow rate (Qmax) and post-void residual (PVR) determinations and volumetric prostate measurements with transrectal ultrasonography (TRUS). Laser and operative times and energy usage were recorded. AUASS, QoL, SHIM, Qmax and PVR were evaluated 4,12 and 24 weeks post-surgery. Serum PSA was obtained at 24 weeks.
There were 200 consecutive men with a median age of 67 (range 48–91) years who underwent GreenLight HPS laser PVP from May 2007 through August 2009. Mean prostate volume and preoperative PSA were 68.1cc (32–160) and 3.4ng/mL (1.8–13.7), respectively. Mean laser and operative times and energy usage were 39 minutes (27–53), 57 minutes (44–125) and 180kJ (100–450), respectively. 190 (95%) of procedures were outpatient-procedures with 81 men (40%) catheter-free at discharge. There were 93% of men who were catheter-free on postoperative day 1. Adverse events included delayed hematuria (>1 week) in 3 (1%), urinary retention requiring foley replacement in 11 (5%), urinary infection in 6 (3%) and retrograde ejaculation in 110 (55%). No urethral strictures or urinary incontinence were noted. Mean AUASS decreased from 22 to 9 and 8 (p < 0.001) while the mean Qmax increased from 8.7 to 21.1, and 22.0 mL/s (p < 0.001) during the follow-up period. The mean decrease in PSA at 6 months was 71%.
At 6 months, our experience further supports that GreenLight HPS laser PVP is safe and effective while providing the patient a minimally-invasive, out-patient surgical option for treating lower urinary tract symptoms secondary to BPH.
GreenLight HPS™ laser PVP is a treatment option for lower urinary tract symptoms (LUTS) secondary to BPH. We review our experience using the GreenLightHPS™ laser system.
We prospectively evaluated our experience with GreenLight HPS™ laser PVP. All patients who failed medical therapy and/or surgery underwent GreenLight HPS™ laser PVP (CW). All had American Urological Association Symptom Score (AUASS), Sexual Health Inventory for Men (SHIM) score, American Society of Anesthesiologists (ASA) risk score, serum prostate specific antigen (PSA), maximum flow rate (Qmax) and post void residual (PVR) determinations and volumetric measurements with transrectal ultrasonography. Transurethral PVP was performed using a GreenLight HPS™ side-firing laser system.
There were 181 consecutive patients who were identified, having a mean age of 67.8 ± 9.7 years. The mean prostate volume was 69.2 ± 40.7 mL and the mean ASA score was 2.3 ± 0.7. Mean laser time, operating time and energy usage were 13.6 ± 9.9 minutes, 31.9 ± 22.8 minutes and 90.9 ± 67.5 kJ, respectively. All were outpatient procedures with 99 (54.7%) patients catheter-free at discharge. Of the patients who were discharged with a urethral catheter, 61 (33.7%) patients had it removed the following morning. 9 (5.0%) patients developed a urinary tract infection. Fourteen (7.7%) patients had persistent nonsignificant hematuria >1 week. One (0.6%) bladder neck contracture and no urethral strictures were noted. Mean AUASS decreased from 23 to 8, 7, 5, 5, 4, 3, 3 and 2 (p < 0.05) at 1 and 4 weeks and 3, 6, 12, 18, 24 and 36 months, respectively. Qmax values also showed statistical significant improvement (p < 0.05) during the follow-up period. The SHIM score did not change postoperatively.
Our intermediate results suggest that GreenLight HPS™ laser PVP is safe and effective for the treatment of LUTS secondary to BPH.
The most widely-accepted explanation for the development of abnormal collagen deposits in the tunica albuginea covering of the penis, known as Peyronie’s disease (PD) is that it follows aberrant wound healing after penile injury. It is suggested that following trauma to the erect penis, probably during sexual intercourse, microscopic tears develop in the tunica albuginea. Contemporary data suggests incidence in 5–9% of men, as “tunical scarring” results in development of penile plaques and subsequent penile curvature or other deformity during erection and in some, erectile dysfunction. On the other hand, data to support the involvement of penile trauma in precipitating PD are inconclusive. Interestingly, while the testes have a similar tunica albuginea covering to that of the penis, testicular injury (direct trauma) does not seem to result in tunical scarring. The aim of this study was to clarify the prevalence of penile injury in a large contemporary cohort of patients diagnosed with PD.
Patients were evaluated between January 2008 and October 2009 and diagnosed with PD based on history, genitourinary examination and high resolution penile ultrasound (US). Penile US was used to confirm the penile plaques sites, size, and presence/absence of calcification. If erectile function was compromised, color penile US was done. Patients were questioned for injury events (self and/or partner stimulation) to the erect penis prior to the development of penile deformity. Institutional approval was obtained.
The 400 consecutive patients included in this study had a mean age of 52 y and duration of disease prior to presentation of 1.1 y. Plaque distribution was primarily dorsal or dorso-lateral. Calcification of the penile plaques was present in 18% (n = 72) of patients, while only 15% (n = 60) of patients reported history of penile injury. There were no significant differences between the patients with and without history of penile injury regarding age, penile plaque size, site and presence of calcification.
This large prospective series solidifies recent evolving data that penile injury does not appear to be the primary cause of PD; potential causes may include immunological or inflammatory disorders, or as yet unidentified causes.
Previous studies have identified several barriers to effective delivery of men’s health care; in Ontario, there is a recent shift to increased diagnostic and therapeutic decision-making by nurse practitioners, including prescribing privileges. Screening for erectile dysfunction (in the context of both enhanced quality of life and as a window into cardiovascular health), ED treatment options ranging from risk and lifestyle factor modification to pharmacologic intervention, Peyronie’s disease, and low testosterone states have not been adequately addressed in primary care nurse practitioner training. We present results from a pilot project whereby an initial needs assessment was performed, followed by trial small group teaching and re-evaluation of information delivery efficacy.
There were 70 nurse practitioners in the health care network catchment area identified. Initial needs assessment was performed by a broad 8 question (multiple subheading) web-based survey. Data were collated, and areas of interest identified pertaining to non-oncologic core men’s health issues.
ED, Peyronie’s disease, and low testosterone states were seen as areas of knowledge deficiency. Initial speaker curriculum underwent modification following trial small group teaching to enhance educational experience; 20–30 minute presentation followed by group discussion, facilitator provision of key information (including published peer-reviewed manuscripts), and step-wise approaches were prioritized. Permanent web-based availability of programs, and targeted references to web-based sites such as the SMSNA site, were found useful.
The changing landscape of primary care offers an opportunity for enhanced men’s health through targeted education of nurse practitioners and implementation of simple, time-effective screening, diagnosis, and treatment implementation in everyday practice.
In men with mild erectile dysfunction (ED), the risk for diseases associated with ED is unclear, and ED may be overlooked in clinical practice, often because of patient hesitation to seek treatment. We previously showed improved erectile function and high treatment satisfaction with sildenafil in an 8-week, Canadian, double-blind placebo-controlled (DBPC) trial in mild ED (Erectile Function domain of the International Index of Erectile Function [IIEF-EF] score 22–25). Here we assess response to sildenafil (50 mg, adjustable to 25 or 100 mg) in the 6-week open-label (OL) extension (n = 152) and compare the risk for diseases associated with ED in the DBPC trial population (n = 176) relative to a database of 14,537 men enrolled in 67 other DBPC sildenafil trials in ED.
Treatment satisfaction was defined by the Erectile Dysfunction Inventory of Treatment Satisfaction (Index score >50).
At OL end, 93% of men had treatment satisfaction and 77% had no ED (per IIEF-EF score); mean scores on IIEF domains, the Quality of Erection Questionnaire, and analog scales (erection firmness, reliability, and maintenance, and general sexual performance) were >80% of the maximum; and most intercourse occasions had completely hard/fully rigid erections (60%), hardness sufficient for penetration (85%), duration sufficient for successful intercourse (83%), and ejaculation/orgasm (81%). Mild to moderate headache, nasal congestion, and flushing were the most common adverse events. In the mild ED and database populations, most had an organic component to their ED etiology; mean ± SD age was 50 ± 12 vs. 55 ± 11 years, body mass index was 29 ± 5 versus 28 ± 5 kg/m2, and ED duration was 3.5 ± 3.2 vs. 4.6 ± 4.7 years; the prevalence of comorbidities was similar (hypertension [26% vs. 33%], diabetes mellitus [14% vs. 22%], dyslipidemias [13% vs. 12%], hypercholesterolemia [13% vs. 10%], gastroesophageal reflux disease [11% vs. 6%], benign prostatic hyperplasia [10% vs. 10%], depression [6% vs. 6%], and anxiety [4% vs. 2%]).
In men with mild ED, the potential for clinical benefit from sildenafil treatment and the risk for underlying disease are substantial. Inquiry into ED should be part of routine clinical evaluation to facilitate rapid identification and early intervention, including evaluation for underlying cardiovascular risk.
A hydrocele is accumulation of fluid around a testicle, common in general urology practice. Treatment options include observation, aspiration with sclerotherapy, or surgery. The most widely used surgical techniques are the Jaboulay and Lord’s procedure. The Jaboulay technique involves evertion of the sac and suture behind the testis. It is associated with a reduced risk of recurrence, but patients may have an increased risk of hematoma. The Lord’s technique involves plication of the sac, used for small to medium hydroceles. The benefits of this technique are reduced risk of hematoma, there may be a higher risk of recurrence.
We retrospectively reviewed all hydrocelectomies done by two urologists at The Ottawa Hospital from 2005–2009. The rate of successful hydrocele resolution at 3 months was assessed. Results were stratified intra-operative hydrocele volume (<200 cc small, 200–500 cc moderate and >500 cc large) and by surgical technique (Jaboulay vs. Lord’s).
There were 68 hydrocelectomies performed, of which a complete 3 month follow-up was available for 50. A Lord’s technique was used in 35 cases, Jaboulay in 11 and technique was unreported in 22. At 3 months postoperatively, resolution was observed in 66% (33/50) of patients. Patients undergoing Lord’s technique had resolution in 77% of cases (17/22) versus 78% (7/9 cases) of those undergoing a Jaboulay repair. Of the 7 patients without resolution at 3 months, 6 month follow up indicated 3 resolved, 2 were lost to follow up and 2 required aspiration. Those without technique reported had resolution in 44% (7/16) of cases. Of the 9 without resolution at 3 months, 6 month follow up indicated 4 resolved, 3 were lost to follow up and 2 remained. There were 33 hydroceles reported as large, 13 as moderate, 7 as small and 15 unreported with f/u data available for 38. Of large hydroceles 57% (13/23) are resolved at 3 months vs. 50% (5/10) moderately sized hydroceles and 80% (4/5) small hydroceles.
Roughly two thirds of patients have resolution of swelling 3 months after hydrocelectomy. Most patients with swelling have further resolution at 6 months with rare need for repeat surgery or aspiration. Many patients with residual swelling at the initial follow up did not attend further schedule appointments, which may indicate further resolution. The technique of hydrocelectomy did not appear to affect successful resolution but small hydroceles had better results that those with over 200 cc of fluid.
Management of Peyronie’s Disease is still controversial. This includes contra lateral plication or incision of the plaque, and grafting using autologous or homologous grafts did not give satisfactory results. It is aimed at evaluating definitive management using buccal mucosal grafts and geometrical incisions to overcome the curvature.
Eleven patients were included in the series. Eight of them had normal erection. Three had erectile dysfunction being treated by a single oral phosphodiesterase-5 inhibitor and six had associated disease such as Diabetes mellitus, hypertension or hypospadius. All were successfully operated upon. Mean age of patients was 46.6 years. The mean difference in short/long limb of the curve was 1.2 cm. The plaque was incised and the defect was covered by buccal mucosal graft. The International Index of Erectile Function (IIEF-5) and pharmacodynamic colour Doppler study, serum hormone profile and history including partner satisfaction were done pre- and postoperatively (Fig. 1).
Two years of postoperative follow up were documented. Good erection was observed under pharmacodynamic colour Doppler sonog-raphy study 6 months later. All patients have shown 100% penile straightening retaining normal length. All have reported on satisfaction of the partner 6 weeks postoperatively except for a patient who is still far away from his female partner. There was 1.8 mean increase of the IIEF-5. No recurrence was observed during the follow up period (mean 14.8 months).
The use of buccal mucosa and geometrical incisions for surgical management of Peyronie’s Disease gives excellent results and is free of complication or recurrence.
A varicocele remains the most commonly identified correctable cause of male factor infertility. In North America, surgical correction is the most commonly performed technique to treat varicoceles with an expected technical failure rate of less than 5%. An alternative to surgery is selective catheterization and embolization of the gonadal vein using sclerosing agents, tissue adhesives, or detachable coils. The improvements in fertility following varicocele repair appear to be independent of the type of repair, as long as the repair was successful. Our objective was to the review the failure rates of varicocele embolization done for male factor infertility from our institution to determine if these rates were higher than expected with a surgical repair.
Retrospective review of the University of Toronto varicocele database. All of the patients included in the database had clinical varicoceles with ultrasound confirmation. Patients that had ultrasound evidence of a contralateral subclinical varicocele were offered bilateral varicocele embolization.
A total of 158 patients were identified from 2004 to 2008 who underwent embolization for clinical varicocele(s) and male factor infertility. There was 56% (88/158) who underwent attempted bilateral embolization, 43% (68/158) unilateral left sided embolization, and 1.3% (2/158) unilateral right sided embolization. Of those patients who underwent attempted bilateral embolization, there was a 19.3% (17/88) technical failure rate in achieving successful obliteration of the right gonadal vein and a 2.3% (2/88) technical failure rate in the embolization of the left gonadal vein. Of the 2 attempts at unilateral right sided embolization there were no failures (0/2). Of 68 unilateral left sided embolization attempts there was a 4.4% failure rate (3/68). Of all of the right sided embolization attempts, 18.9% failed (17/90), while 3.2% (5/156) of the left sided attempts failed.
This review represents the largest contemporary series of varicocele embolization outcomes currently in the literature. Our 19.3% technical failure rate for bilateral varicocele embolization is higher than the current published rate of 13%. This was almost universally secondary to failure to access the right gonadal vein from the inferior vena cava. This supports our belief that bilateral varicoceles are best managed with a primary microsurgical approach where technical failure rates are expected to be less than 5% based on published data.
The treatment of varicocele includes invasive modalities like Palomo’s operation,microsurgical varicocele ligation and minimally invasive procedures laparoscopic varicocele ligation. Percutaneous embolisation is another attractive option. We prospectively studied the efficacy in terms of ability to access the internal spermatic vein, achievement of satisfactory embolisation documented by absence of flow by follow-up Color Doppler flow studies and changes in semen parameters.
A total of 22 patients with varicocele were treated, amongst them 12 had infertility, 11 had scrotal discomfort and 5 patients had loss of testicular volume. 11% had grade 1, 44.5% had grade 2 and 44.5% had grade 3 varicoceles. As an out-patient procedure, via trans femoral route spermatic vein was cannulated under local anaesthesia. Variable numbers of customized coils prepared locally from 0.035 inch PTFE coated stainless steel guidewires, placed to achieve complete embolisation. Follow-up Doppler Ultrasonography was performed at one month to confirm the reduction of venous diameter and absence of flow. Semen parameters were re-evaluated at 3 months after the procedure.
In 18 patients (81.8%) spermatic vein could be accessed and all of them were successfully embolised. All of them except one had significant reduction in venous diameter on Doppler ultrasonography. The technical failure rate was 18% (n = 4). Seventy-eight percent of the patients had significant improvement in symptomatology. Follow-up semen parameter revealed improvement in sperm counts amongst 70.3% of patients with average increase of 16.2 million/ml in grade 3 and 5.7 million/mL in grade 2 varicocele patients. Sperm morphology and motility had improved in 58.8% & 41.1% of the patients respectively. We noted that greater the degree of varicocele greater the symptomatic improvement as well as semen quality improvement.
Percutaneous embolisation of varicocele is incision-free and out-patient procedure. It avoids testicular arterial injury which is a possibility for ligation procedures. Embolisation can be achieved by balloons, sclerosing agents, hot contrast materials or stainless steel coils. Customized coils used in the present study had reduced the cost substantially without affecting the efficacy. Hospital stay is very short. Semen parameter improvements are comparable to traditional non-embolisation procedures. However, it needs expertise in the field of angiography.
The mini-incision vasectomy reversal (MIVR) using no-scalpel vasectomy principles and instruments (Urology, 2008) was developed with the goal of reducing surgical morbidity and expediting recovery, while preserving high quality patient outcomes. The current study details the patency outcomes of a large series of patients following MIVR.
From May 2008 to November 2009, 105 consecutive vasectomy reversals (VR) were reviewed (86% bilateral VV, 9% mixed VV/VE, 5% bilateral VE). Among the bilateral VV group, 48% had a bilateral MIVR, 23% had a mixed MIVR/traditional incision VR and 29% had a bilateral traditional incision VR. MIVR were performed via a sub-centimeter incision after the vas was captured and brought through the skin using the no-scalpel vasectomy ring forceps applied to the site of vassal occlusion. Traditional VR were performed via a high scrotal incision with delivery of the testis as necessary. Traditional incisions were indicated if there was uncertainly as to the location of the vasectomy occlusion site as well as for wide vasal gaps, large sperm granulomas, re-do reversals and patients requiring VE. Semen analyses were obtained 2 and 4 months postoperatively, and then every 3 months until pregnancy was achieved. Patency was defined as the presence of motile sperm in the ejaculate following VR.
Mean patient age and vasal occlusion interval was 39 years and 6.8 years, respectively. Mean follow up was 9 months. Postoperative patency rates were 96%, 100% and 94% for the bilateral MIVR, mixed MIVR/traditional incision and bilateral traditional incision VR groups, respectively (p = 0.7). Among patients with available follow up following bilateral VV, mean semen parameters are summarized in Table 1. No patients with an initially patent bilateral MIVR have become azoospermic.
MIVR is technically feasible in a significant proportion of men undergoing VR and yields patency rates similar to more traditional approaches to VR. We are currently reviewing postoperative morbidity and pain outcomes with validated instruments.
|% patent||Sperm conc. mil/ml||% motile||% normal morphology||Total motile count|
|Bilateral MIVR (n = 22)||96%||46||40%||36%||49|
|MIVR - Traditional (n = 13)||100%||39||42%||44%||46|
|Traditional (n = 17)||94%||33||30%||31%||48|
|p = 0.7||p = 0.6||p = 0.4||p = 0.4||p = 0.9|
The sonic hedgehog (SHH) signal transduction pathway plays a central role in cell growth and differentiation during development. Its expression and activity have been shown to be aberrant in different kinds of cancer, but little is known about its role in kidney cancer. In the present study we analyzed expression of components of the SHH pathway in renal cell carcinoma.
Immunohistochemistry was performed on a commercial tissue microarray (TMA) containing 420 cores from 210 specimens obtained from partial or radical nephrectomy (US Biomax, Inc., Rockville, MD). All cores were clear cell carcinoma. The TMA was stained for the ligand sonic hedgehog, the receptor Smoothened and the receptor Patched. Staining intensity was graded from 0–3 by a pathologist (LF) in blinded fashion. A score was derived by multiplying the staining intensity by the percentage of surface area of the core with positive staining. These scores were normalized to the mean score of 28 cores of normal kidney on the TMA. The Kruskal Wallis test was used to compare staining score to pathologic stage and grade. There was no available clinical follow-up data. Expression of pathway intermediates was examined by Western blot in a single RCC cell line (CAKI-2) compared to a panel of bladder and prostate carcinoma cell lines.
Sonic hedgehog ligand expression was low in normal kidney and increased by grade in RCC (p < 0.001). Patched expression also increased by grade in RCC (p < 0.001). Smoothened expression, in contrast, was highest in normal kidney (p < 0.001), decreased by 50% in low grade tumours, and increased again in intermediate and high grade tumours. Parallel but less pronounced changes were seen with tumour stage. All three components, as well as the ligand Indian hedgehog and the downstream effectors Gli-1 and Gli-2 were expressed at high levels in CAKI-2 when compared to prostate and bladder carcinoma cell lines, which is indicative of SHH pathway activity.
These results offer some preliminary indication that the regulation of the sonic hedgehog signaling pathway may be aberrant in renal cell carcinoma. Further investigations will be necessary to evaluate this pathway as a potential target for novel therapeutic agents.
There is mounting evidence on the adverse effect of treatment induced renal function impairment on the survival of patients treated for renal tumours. Patients with solitary kidneys are clearly at risk for renal deterioration following even nephron-sparing surgery. We evaluate the effect of open partial nephrectomy on postoperative renal function in patients with a solitary kidney.
Of 145 consecutive patients who underwent partial nephrectomy at The Ottawa Hospital from 2002 to 2008, 17 had tumour in a solitary kidney. They underwent open partial nephrectomy with hilar clamping and surface renal cooling in all but one patient. Renal surface cooling was achieved using ice-slush for 10–15 minutes. Renal function was estimated by calculating creatinine clearance (CrCl) using Cockroft-Gault formula before and 3 months after the operation. 4 patients (23.5%) required short-term hemodialysis (HD) and only one patient (5.8%) required long-term HD. Univariate logistic regression analysis examining the effect of age at diagnosis, ischemia time, tumour size, preoperative CrCl, pre-existing diabetes mellitus and hypertension on 3 months postoperative CrCl and the need for short and long-term HD were performed.
Mean patient age at diagnosis was 61.4 years with a mean follow-up period of 32.9 months. Mean tumour size was 2.86 cm and mean cold ischemia time was 39.7 minutes. Mean CrCl at baseline and 3 months postoperative were 72 and 61.8 ml/s respectively (p-value =0.008). Postoperative CrCl was significantly affected by patient’s age (p-value = 0.006) and baseline CrCl (p-value < 0.0001). Patient age, tumour size, ischemia time, baseline renal function and co-morbidity with diabetes or hypertension were not significant factors in determining the need for short or long-term HD.
Open partial nephrectomy results in a minor decrease in renal function in patients with a solitary kidney. This change in renal function although significant may not be clinically impactful. Patient age and preoperative renal function are important factors in predicting postoperative CrCl. The need for short and long-term HD was not determined by any preoperative or operative factor. Open partial nephrectomy should continue to be considered the treatment of choice in patients with tumours in a solitary kidney.
Most new renal masses are now diagnosed incidentally and frequently while still small in size. Most of these small renal masses (SRM) are treated with partial nephrectomy, procedure which has a significant amount of complications. Multiple series have reported a high proportion (up to 46%) of benign histology after surgical resection of these SRMs. There is a clear need for accurate prediction of benign disease. Multiple preoperative factors such as sex, age, tumour size and location have been implicated in the prediction of benign histology. We aimed to apply classification tree algorithms to discriminate between benign and malignant histology when SRMs are being evaluated preoperatively.
A classification tree was developed based on a cohort of 327 patients who underwent surgical management for presumed renal cell carcinoma <5 cm in largest diameter at our institution between July 1, 2001 and June 30, 2009. Age, sex, tumour size (largest bi-dimensional diameter in cm), tumour location (central vs. peripheral), degree of endophytic component (1–100%) and tumour axis location (according to the three renal axes) were used to develop the model.
The overall incidence of benign disease was 11%. The classification tree partitioned the subjects into four disjoint sets differing in risk of benign histology based on a minimum of one and a maximum of three predictors: tumour location, degree of endophytic component and tumour size. As an example in one branch of the tree, patients who had peripheral tumours, with a >45% endophytic component, and a tumour volume of less than 4.9 cc had a 57.2% chance of having benign histology. Overall, patients who had central/hilar and peripheral tumours had a 6.4% and 20.4% chance of having benign histology, respectively. The cross-validated estimate accuracy of the model is 89.6% with a 95% CI (85.8, 92.7).
We demonstrate that we can predict benign disease using this model with an 89.6% accuracy. We observed that in this era of incidentalomas, tumour location and degree of endophytic component have a better predictive ability than tumour size when differentiating benign vs. malignant lesions. We believe that classification trees are easier to use in the clinical setting when compared with logistic regression models as they mimic the clinician’s thought process. This classification tree will be validated with an external dataset.
Active surveillance (AS) is the treatment of choice for patients with small renal masses (SRM) who are not surgical candidates, due to existing comorbidities or patient choice. It has been shown that most SRMs grow slowly, but there are some masses that grow rapidly, requiring treatment or progressing to metastatic disease. Patient and tumour characteristics related to this more aggressive behavior have been poorly studied. We report our analysis of a prospective cohort with a median follow-up of 35 months.
This study is based on a prospectively accrued cohort of 67 patients who underwent AS between July 1 2001 and June 30 2009 with a minimum follow-up time of 6 months. Age, sex, symptoms at presentation, tumour size at diagnosis (diameter in cm), tumour location (central/peripheral), degree of endophytic component (1–100%) and tumour consistency (solid/cystic) were used to develop a predictive model using Binary Recursive Partitioning Analysis.
Median follow-up was 35 (9–96) months. Mean patient age was 74.1 (52–91) and 59.7% were male. There were 94% of the masses which were diagnosed incidentally; 58.2% of the masses had a peripheral location (41.8% central/hilar) with a mean endophytic component of 51.9%, and 88.1% of the masses were solid (11.9% cystic). Mean largest tumour diameter at diagnosis was 2.5 cm (range 0.8–5.4). One (1.5%) patient developed and died of metastatic disease while 11 (16.4%) went on to have surgery (all renal cell carcinoma). Seven (10.4%) patients died of other causes while 48 (71.6%) remain on AS. Average growth rate for the entire cohort was 0.22 cm/year. Binary recursive partitioning yielded a cut off point of 2.45 cm (95% CI 1.75, 2.65) for the diameter at diagnosis which optimally separated those masses with slower (0.17 cm/year) and faster (0.28 cm/year) growth rates. All other variables included in the model did not provide independent or additional prognostic information.
Based on this series of patients on AS with a mean follow-up time of 3 years we confirm that most renal masses grow slowly and carry a low metastatic potential. Two distinct growth rates are identifiable and can be predicted based on tumour size. Masses that are ≥2.45 cm in largest diameter at diagnosis grow faster than smaller masses. Although this data provides further insight into the natural history of untreated renal masses, it should not be extrapolated to a population of surgical candidates who tend to be younger and have a higher proportion of central lesions.
We assessed the rate of metastatic renal cell carcinoma (mRCC) at diagnosis in a large population-based tumour registry.
Between 1988 and 2006, 87842 patients were identified within 17 Surveillance, Epidemiology and End Results (SEER) registries with tissue-proven diagnosis of RCC of all stages. We examined the rates of mRCC at diagnosis throughout the study period. Multivariable logistic regression models examined the impact of year of diagnosis quartiles (1988–1992 vs. 1993–1997 vs. 1998–2002 vs. 2003–2006) on mRCC rates after adjusting for patient age, gender, race and socioeconomic status.
The overall rate of mRCC was 19.1% and it decreased from 23.8% in the first year quartile to 16.5% over the study period (χ2 trend: p < 0.001). The decrease in mRCC rates was more pronounced in females (−8.6%) than in males (−6.9%), in older individuals (−12.3% in ≥80 years) than in younger patients (−7.0% in <50 years), in African-American (−9.7%) than in Caucasian patients (−7.3%), and in patients within the highest socioeconomic status quartile (−8.9%) relative to individuals within the lowest socioeconomic status quartile (−7.3%). In multivariable logistic regression models more advanced age (p < 0.001), male gender (p < 0.001), race other than Caucasian and African-American (p = 0.02) and lower socioeconomic status (p < 0.001) represented independent predictors of mRCC diagnosis. Finally, more contemporary year of diagnosis remained the foremost predictor of lower rate of mRCC at initial diagnosis (p < 0.001).
Our findings are highly encouraging and suggest that a larger proportion of patients will harbor curable or highly treatable stages of RCC. Conversely, an increasingly smaller proportion of mRCC will hopefully contribute to the overall RCC patient population. The increased use of imaging studies may represent an explanation for the observed results.
Partial nephrectomy (PN) represents the treatment modality of choice for patients with small renal masses. We examined the rates of PN in patients with histologically proven small renal masses within a large population-based tumour registry.
Within the 17 registries from the Surveillance, Epidemiology and End Results database, between the years 1988 and 2006, we identified 20880 patients treated with either a partial or radical nephrectomy for T1aN0M0 histologically proven renal cell carcinoma. Trends, proportions, and multivariable logistic regression models were generated to assess the use of partial versus radical nephrectomy in this cohort.
Overall, 30.1% of patients underwent a PN between 1988 and 2006. The annual rates of PN use increased from 7.0 to 42.1% throughout the entire study period (relative increase: 6.0%, chi-square trend: p < 0.001). For tumours smaller or equal to 2.0 centimeters, the use of PN increased from 14.0 to 58.3% (relative increase: 4.2%, chi-square trend: p < 0.001) vs. 5.1 to 35.5% (relative increase: 7.0%, chi-square trend: p < 0.001) in tumours sized between 2.1 to 4.0 centimeters within the study period. Of all patients who received a PN, most were Caucasian (84.0%) and male (63.0%). PNs were more frequent in patients aged between 60–69 years old (27.8%) and least common in octogenarians (3.9%). Metropolitan areas showed the highest rate of PN being performed (91.0%). Additionally, most PN were performed in counties where the estimated median family income ranged between 45 to 75 thousand dollars (72.7%) vs. lower median family income counties (range 18 to 35 thousand dollars). Finally, most PNs were performed in the most contemporary year quartile (37.2%). Multivariable models revealed that males were 1.2 times more likely to undergo a PN relative to female gender vs. 1.2 times for Caucasians compared to African Americans and 2.3 times in patients aged less than 50 years old relative to octogenarians (all p < 0.001). Moreover, PN are 2.7 times more likely used in tumours sized less or equal to 2.0 centimeters relative to those larger than 2.0 centimeters (p < 0.001). Finally, PN was up to 4 times higher in more contemporary years (p < 0.001).
The rate of PN increased over the study period. As many as 48.1% of small renal masses less or equal to 2.0 centimeters were treated with PN. Only 24.4% of tumours sized from 2.1 to 4.0 centimeters were treated with a PN. Despite a clear increase in the rates of PN use over time, more emphasis needs to be placed on its benefit over radical nephrectomy to further encourage its use in clinical practice.
The National Comprehensive Cancer Network guidelines suggest the use of non-surgical management (NSM) of small renal masses in patients with multiple comorbidities and in those with limited life expectancy. We examined the rates of non cancer-related mortality (NCRM) in this category of patients.
Within the Surveillance, Epidemiology, and End Results database, we identified 1404 NSM patients for T1a renal cell carcinoma between the years 1988 and 2006. NCRM rates were assessed using the Kaplan-Meier and life table method.
The overall 2-year NCRM survival rate was 67.9%. Between 1988 and 2004, the 2-year NCRM rates decreased from 37.3% to 29.1% (all log-rank p ≤ 0.01). NCRM decreased from 27.3 to 25.2% in patients aged less than 50 years for the same time points (log-rank p < 0.001). In patients aged 80 years and older, NCRM rates for the same time points increased from 30.9 to 35.4% (log-rank p = 0.2). In males, the NCRM rates decreased respectively from 41.3 to 31.5% vs. 32.9 to 24.6% in females (all log-rank tests p ≤ 0.006). Finally, NCRM rates decreased from 37.0 to 28.0% in Caucasians (log-rank p = 0.005). In African Americans, the rates remained relatively unchanged (39.1 to 38.4%, log-rank p = 0.6). NCRM was most commonly attributed to diseases of the heart (25.7%), lung cancer (9.9%), cerebrovascular diseases (4.3%), and other unspecified malignancies (5.2%).
Based on these results, older patients are more likely to die of NCRM than their younger counterparts. Similarly, males and African Americans are more prone to die of other causes than their female and Caucasian counterparts. The rate of NCRM rates have decreased in NSM patients for histologically proven small renal masses in renal cell carcinoma. This implies that the indication for NSM in these patients may have become less selective. Therefore, NSM may require a re-appraisal.
Percutaneous needle core biopsy is becoming established in the management of small renal masses ≤4 cm (SRMs). Numerous recent series have reported success rates of ≥80% with excellent predictive accuracy. Indeterminate or non-diagnostic results continue to be a problem. We present the results of a large biopsy series with outcomes of the non-diagnostic biopsies.
A prospectively maintained database of patients undergoing renal mass biopsy was analyzed to determine the pathology and outcomes of SRM biopsies. Reports of “indeterminate” results included insufficient material, normal kidney or non-renal tissue. Repeat biopsy has recently been recommended and the correlation with the first biopsy as well as outcome were analyzed.
Three hundred sixteen (316) biopsies were performed (SRM mean diameter 2.5 cm) between January 2000 and October 2009. Biopsy was diagnostic in 266 cases (84.2%) and non-diagnostic in 50 cases (15.8%). Among diagnostic biopsies, 203 (76.3%) were malignant, 95.1% of which were renal cell carcinoma (RCC). Histologic subtyping and grading of RCC was possible in 87.6% and 62.7% of cases, respectively. Twelve (12/50 or 24%) of the non-diagnostic biopsies were taken at the time of radiofrequency ablation. Four patients underwent surgical resection of the mass, and 23 were managed by active surveillance. Repeat biopsy was performed in 10 of the 50 non-diagnostic cases, and a diagnosis was possible in 9 (90%). Seven lesions were malignant, and 2 were oncocytic neoplasms. Larger tumour size and a solid nature were found to predict a successful biopsy. Minor complications were experienced in 10.3% of cases, with no major bleeding noted, and no seeding of the biopsy tract.
Percutaneous biopsy can be performed safely and accurately in the investigation of renal masses 4cm or less in size. In those cases in which the biopsy is indeterminate, repeat biopsy can be performed with similar accuracy, thus providing a diagnosis in the majority of patients.
Laparoscopic radical nephrectomy is evolving as the standard of care for cancerous renal masses. Upon complete dissection of the kidney, the specimen may be removed via muscle-splitting expansion of an expanded port site (EPS) or a Pfannenstiel (PFN) incision (non-muscle splitting). In a recent retrospective analysis, our group demonstrated a statistically significant reduction in hospital stay and narcotic use in patients who underwent PFN extraction. We present the results of a prospective randomized study investigating potential differences between PFN and EPS specimen extraction.
Based on a sample size calculation (power 90%, p < 0.05), a series of 97 consecutive patients (2005–2009) were randomized preop-eratively to undergo either EPS or PFN specimen extraction after transperitoneal laparoscopic nephrectomy for renal malignancy. Postoperative follow-up (FU) occurred at 1 week, 6 weeks and 6 months with standardized questionnaires including a visual analog pain score, return to work, physical recovery, operative satisfaction, cosmesis satisfaction, and whether patients would repeat the operation, choose the same incision and recommend the same incision to others. Statistical analysis was conducted utilizing a two-tailed Student’s t-test with two-sample unequal variance at each clinical encounter while a Fisher’s exact test was employed at the 6 month visit for repeat operation, cosmesis and same incision.
Target patient accrual was attained with 97 patients enrolled and 80 patients having completed 6 month FU: 44 EPS and 36 PFN. Wound infection occurred in 3 patients (2 PFN and 1 EPS). There were no statistically significant differences (p < 0.05) in pain scores, return to work, physical recovery, operative satisfaction and cosmesis at 1 week, 6 weeks and 6 months FU. At 6 months FU, there were no significant differences with respect to repeating the same operation, using the same incision and recommending the incision to others.
To our knowledge this is the first prospective randomized study comparing PFN and EPS specimen extraction in laparoscopic radical nephrectomy. Our FU results at 1 week, 6 week and 6 months did not reveal any statistically significant difference in pain scores, satisfaction, recovery or cosmesis.
Partial nephrectomy (PN) is frequently used. However, its rates could still be increased, especially in patients with T1a renal cell carcinomas (RCC). The rationale for maximizing PN rates may reside in the protective effect of PN on non-RCC related events. We tested this hypothesis in a large population-based cohort.
Between 1988 and 2006, 23613 patients underwent a PN (n=7048; 29.8%) or a radical nephrectomy (RN) (n=16565; 70.2%) for pT1apN0M0 RCC within 17 Surveillance, Epidemiology and End Results (SEER) registries. Cumulative incidence plots addressed other-cause mortality (OCM) rates of PN vs. RN patients after accounting for cancer-specific mortality. Finally, multivariable competing-risks regression models addressed OCM after PN vs. RN after adjusting for age, gender, race, tumour size, histological subtype, tumour grade and year of diagnosis.
Overall, cardiovascular disease, cerebrovascular disease and lung cancer were the three most frequent non-RCC related causes of death. In univariable analyses, RN was associated with a 1.52 (95% CI: 1.40–1.66; p < 0.001) increase in OCM relative to PN, which translated into a 5.01% and 8.63% absolute increase in mortality at 5 and 10 years after surgery respectively. In multivariable competing-risks regression models RN was still associated with a statistically significant increase in OCM rates relative to PN (HR: 1.29; 95% CI: 1.18–1.41; p < 0.001).
Patients treated with RN for T1a RCC have higher OCM rates than PN patients even after adjustment for various patient and tumour characteristics. In consequence, PN should be attempted whenever technically feasible in order to decrease non-RCC related deaths.
As the incidence of radiologic detection of renal masses increases, poor surgical candidates are often offered either percutaneous renal cryoablation (PRC) or transperitoneal laparoscopic renal cryoablation (TLRC). This multicentre experience compares PRC and TLRC.
Between 09/1998 and 02/2009, retrospective review of our PRC and TLRC experience was performed. Patients with a minimum 12 month follow-up were included for analysis. Post treatment surveillance consisted of laboratory studies and imaging at regular intervals. Treatment failure was considered if persistent mass enhancement or interval tumour growth was evident on radiography. Repeat biopsy and retreatment were recommended in the event of tumour recurrence.
Sixty-one (67.2% male; 32.8% female) patients underwent PRC, having a mean body mass index (BMI) of 30.2 ± 6.4 kg/m2. 81 (58.0% male; 42.0% female) patients underwent TLRC, having a mean BMI of 29.8 ± 6.6 kg/m2 (p = 0.770). The average patient age was 69.1 ± 11.5 (PRC) and 65.7 ± 10.0 (TLRC) years (p = 0.062). The prevalence of comorbid conditions in the PRC and TLRC cohorts was: 21.3 ± 41.3% vs. 33.8 ± 47.6% diabetes mellitus (p = 0.106), 72.1 ± 45.2% vs. 78.8 ± 41.2% hypertension (p = 0.366) and 42.6 ± 49.9% vs. 58.8 ± 49.5% smoking history (p = 0.058), respectively. Mean tumour size was 2.7 ± 1.1 (PRC) and 2.5 ± 0.8 (TLRC) cm (p = 0.153). 76.4 ± 42.8% (PRC) and 60.3 ± 49.3% (TLRC) renal masses (p = 0.052) were biopsy-confirmed renal cell carcinoma. The mean follow-up was 31.0 ± 14.1 (PRC) and 39.8 ± 22.6 (TLRC) months (p = 0.009), with local tumour recurrence noted in 15.0 ± 36.0% (PRC) and 5.0 ± 21.9% (TLRC) of kidneys (p = 0.044), respectively. In the PRC cohort, disease-free survival (DFS) and overall survival (OS) were 93.3 ± 25.2% and 91.7 ± 27.9%, with 4 patients having evidence of disease at last follow-up. DFS and OS was 92.5 ± 26.5% and 93.8 ± 24.4% in the TLRC group, with 6 patients having evidence of disease at last follow-up. DFS (p = 0.851) and OS (p = 0.639) were similar.
In this multicentre study of well-matched PRC and TLRC cohorts, PRC had higher primary treatment failure rates than TLRC. However, a greater percentage undergoing PRC had biopsy-confirmed RCC. DFS and OS survival were similar in both groups. Additional follow-up is required to determine if the approach, either PRC or TLRC, truly affects the treatment outcomes.
Inositol hexakisphosphate (IP6) is a naturally occurring phytochemical abundant in soy, cereals and legumes. We have shown that IP6 may be a promising anti-cancer agent in prostate cancer (PCa). Definite mechanisms remain to be established as IP6 potentially acts by targeting several signaling pathways, as well as to cause cell cycle arrest and to induce cell death. When the IP6 salt is reconstituted in water, the solution has a pH of 12, which is not apt for consumption. The pH must thus be adjusted to 7 prior to use. Our objective was to evaluate to biological activities of IP6 at various pH levels.
The hormone-refractory PC3 cell line was stimulated for up to 72 hours with IP6 at pH 5, pH 7 and pH 12. Several parameters, such as metabolic activity (WST1), cell cycle progression (FACS), cell proliferation (cell counting) were measured to evaluate IP6 effects. The phosphorylation status of several proteins documented to be activated following IP6 stimulation was evaluated by Western Blot. All experiments were compared to water at pH 5, 7 and 12, which had no effect on the various biological activities monitored.
At the three pH studied, IP6 induced a significant reduction in the metabolic activity and cellular proliferation of PC3 cells. Following a 24 hr stimulation with 5 mM of IP6, the IP6 at pH 12 reduced the metabolic rate by 89,3 % and IP6 at pH 5 by 78,9%, compared to only 39,6% with the IP6 at pH 7. As for cellular proliferation, following a 72 hr stimulation, IP6 at pH 12 significantly reduced cell number compared to controls by 60.4 % (p = 0.014, T-test) (46.9% for pH 5 and 46.6% at pH 7). There was no evidence of cell cycle arrest at the three pH studied, however a sub-G1 peak was observed only with IP6 at pH 12. Finally, only IP6 at pH 12 induced significant reduction in phospho-AKT, phospho-PDK1 as well as PARP expression following a treatment at pH 12.
We are the first group to report on the effect of pH on the biological activity of IP6. Our results demonstrate that pH modulation has a significant effect on the activity of this phytochemical agent.
The significant immunological boost following androgen depletion therapy (ADT) illustrates the immunosuppressive potential of androgens in prostate cancer (PCa). Since the expression of arginases appears to be one of the mechanisms involved in this immunosuppression, it is of interest to determine whether androgens regulate their expression. Our objectives are to evaluate the in vitro and in vivo expression of arginase in PCa cell lines and primary tumours.
The expression of the two isoforms of arginase (ARG1 and ARG2) was evaluated in vitro using LNCaP cells stimulated with 10 nM of R1881. In vivo expression was evaluated by immunohistochemistry using tissue micro-arrays (TMAs) containing samples from 224 patients. The TMAs included prostate tissues that was normal, non-malignant adjacent to tumour, PIN, hormone sensitive and hormone refractory. One TMA also contained samples from 36 patients treated with ADT prior to surgery. Arginase activity was quantified using an enzymatic assay and HPLC measurements of L-arginine concentration. Cytokine production was determined by ELISA.
LNCaP cells expressed the highest levels of ARG2, whereas no ARG2 expression was detected in Du145 or PC3 cells. ARG1 expression was present in LNCaP, Du145 and PC3 cells. Androgen stimulation led to an overexpression of ARG1 and ARG2 in LNCaP cells. This overex-pression was accompanied by an increase in arginase activity and L-arginine metabolism. In vivo, ADT exposed patients expressed less ARG2 than control patients (p < 0.001, T-test). The androgen-stimulated expression of ARG1 and ARG2 was independent of AR expression (siRNA studies) and AR activity (bicalutamide treatment). IL-8, also overexpressed by androgens in LNCaP cells, was able to induce the expression of ARG1 and ARG2 independently of androgens.
Our results demonstrate that the presence of androgens favors the expression of ARG1 and ARG2 both in vitro and in vivo. Our data supports the notion that the regulation of arginase expression may be independent of the androgen receptor and be partly regulated by IL-8. Further work is ongoing to characterize the immunosuppressive microenvironment in PCa in order to improve the efficacy of immunotherapy.
Prostate cancer (PCa) is the most common internal malignancy and the second most frequent cause of cancer death in Canadian men. Capsaicin, the active compound in chilli peppers has been recently investigated for its protective effects on PCa. Well-established as a pain reliever, capsaicin acts mainly on the transient receptor potential vanilloid (TRPV)-1 and the TRPV6 receptor. These receptors are expressed in PCa cells and can facilitate the inflow of intracellular calcium. Lycopene is an antioxidant found in tomatoes intensely investigated in PCa research. Although the chemopreventive effects of lycopene as a single agent remains controversial, combination studies support its protective properties. Our present study aims to investigate the chemopreventive effect of capsaicin in combination with lycopene. We have found that treating PCa cells with capsaicin and lycopene alone and combined, reduces proliferation and induces apoptosis. Mechanistic studies examining this relationship have not been well established. We hypothesize that capsaicin and lycopene in combination reduce proliferation and induce apoptosis via the TRPV6 and TRPV1 receptor in PCa cells in vitro.
Two human PCa cell lines (PC3 and LNCaP) were analyzed. Cells were incubated for 72 hours with capsaicin alone or combined with lycopene. Using the MTS assay proliferation was measured. LNCaP cells were treated with capsaicin and lycopene and alterations in the expression of TRPV6, TRPV1, androgen receptor (AR), PSA, cell-regulatory molecules and apoptotic markers were assessed by Western Blot analysis.
A significant decrease in proliferation was observed in LNCaP and PC3 cells treated with capsaicin alone (P< 0.05) and combined with lycopene (p < 0.001). Western blot analysis revealed a reduction in AR and PSA expression and an up-regulation of p27 and cleaved PARP, indicating cell-cycle arrest and apoptosis. Correspondingly, an increase in TRPV6 and TRPV1 expression was found in cells treated with capsaicin and lycopene. A plausible mechanism of action for this combination of dietary agents is currently being investigated.
We have shown for the first time that the TRPV6 and TRPV1 receptors may play an important role in capsaicin and lycopene mediated cell-cycle arrest and apoptosis in human PCa cells. These studies may eventually help identify patients likely to benefit from the use of capsaicin in combination with lycopene. Understanding the mechanism of these dietary agents may help improve strategies for PCa patients reducing morbidities associated with conventional therapies.
Inflammation is part of the host response to stress induced by internal or external environmental stimuli. When inflammation becomes recurrent or chronic, it may contribute to the development of human cancers. Inflammation is controlled by the release of various mediators of the immune response. Elevated inflammatory cytokine levels in serum, such as interleukin (IL)-6, have been associated with metastasis-related morbidity in prostate cancer (PCa) patients. We were the first to publish that high IKKe expression results in its nuclear translocation and an increase of IL-6 promoter stimulation. These novel observations suggest that IKKe nuclear translocation leads to the nuclear activation of several transcription factors that control inflammatory cytokine gene expression, particularly IL-6 which could act as a growth factor for PCa cells.
We developed a sub-cutaneous xenograft PCa models able to control inducible IKKe expression. This model makes use of the doxycy-cline- (dox-) inducible PC-3-6TR-shIKKe cells, as well as shLacZ-inducible controls. The cells are mixed with matrigel prior to injection into the flank of SCID mice to limit their spread and to allow the formation of better defined tumours. Dox is delivered through dox-supplemented food (625 mg/kg) to minimize mouse stress. Mice were sacrificed when the tumour volume reached 2,500 mm3 according to the CIPA recommendations.
We performed a large-scale experiment (48 mice) to study the effect of IKKe depletion on PC-3-6TR-shIKKe cell proliferation in vivo. No dehydratation or weight loss was observed in control or IKKe-depleted mice fed with the dox-supplemented diet. We observed an important decrease of the PC-3-6TR-shIKKe xenograft proliferation in SCID mice fed with the dox-supplemented diet. Moreover, PC-3-6TR-shIKKe mice fed with normal diet and all PC-3-6TR-shLacZ control mice reached the predefined tumour volume more than 20 days before PC-3-6TR-shIKKe mice fed with dox-diet.
These results provide solid evidences for a role of IKKe in PCa cell proliferation and survival. We believe that a better understanding of IKKe involvement in PCa may advance our understanding of PCa progression and lead to novel therapeutics options.
The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for bladder cancer and other cancers. Previously, we reported that oncolytic VSV are potent agents for intravesical treatment of high risk bladder cancer. VSV preferentially targeted bladder cancer cells resistant to type I interferon (IFN) treatment. The goal of the current study was to further elucidate the nature of the molecular defect of IFN signaling by which bladder cancer cells become susceptible to VSV infection.
Using a tissue microarray (TMA) composed of human bladder cancer cores, the expressions of IFN pathway-related proteins were examined. The expression of type I IFN receptor (IFNAR) were evaluated in superficial (RT4 and RT112) and invasive bladder cancer cell lines (KU7-luc and UMUC3), and then the association of IFNAR expression levels with the susceptibility to IFN treatment or VSV-induced cell lysis were analyzed. To confirm the hypothesis that down-regulation of IFNAR in bladder cancer cells may be a molecular mechanism responsible for resistance to type I IFN treatment and sensitivity to VSV oncolysis, the effect of siRNA knockdown of IFNAR or blocking IFNAR with a neutralizing antibody in RT4 or KU7-luc cells was evaluated.
The results of TMA showed that the expression of IFNAR was decreased relative to normal bladder tissue. Advanced bladder cancers had even lower expression of IFNAR compared to superficial bladder cancers. Further, invasive bladder cancer cells susceptible to VSV-induced lysis (KU7-luc and UMUC3) had lower expression of IFNAR than resistant superficial cell lines (RT4 and RT112). SiRNA knockdown of IFNAR indeed facilitated replication of VSV in cells previously resistant to VSV treatment and promote VSV-induced cell lysis in those cell lines. Blocking IFNAR with a neutralizing antibody showed a similar effect.
Down-regulation of IFNAR in bladder cancer may be one of the primary molecular mechanisms for clinical IFN resistance. However, this also facilitates VSV replication and oncolysis in high risk bladder cancers and provides a basis for selecting bladder cancer patients for oncolytic VSV therapy in future clinical trials.
Macrophage inhibitory factor (MIF) is an important chemokine influencing progression of prostate cancer. We have demonstrated that tumour hypoxia mediates many factors leading to a malignant phenotype in prostate cancer, including invasion, metastases and drug-resistance. Such hypoxia-induced phenotypes can be attenuated by manipulating nitric oxide (NO) signaling through classic, cGMP mediated pathways. The aim of this study was to determine the role of NO signalling in hypoxia-induced upregulation of MIF in prostate carcinoma cells.
MIF production by DU-145 prostate cancer cells (as well as the MDA breast cancer cell line) was determined by ELISA in different oxygen culture conditions (0.5–20% O2). The role of NO signalling in hypoxia-mediated upregulation of MIF was determined by pharmacologic inhibitors and mimics of classic NO signalling with 10 nM GTN, 100 M L-NMMA as well as non-hydrolysable analogue of cGMP, 8-bromo-cGMP (10 nM).
These studies demonstrate that exposure of DU145 (as well as the MDA cell lines) to low oxygen tension for 24 hours consistently increased the secretion of MIF into the supernatant (1720 ± 245 ng/mL vs. 240 ± 46 ng/ml, p < 0.05). Incubation of the cell lines with the inhibitor of nitric oxide synthase L-NMMA in 20% oxygen resulted in a similar increase in MIF secretion (832 ± 66 ng/ml vs. 220 ± 33 ng/ml, p < 0.029). Restoring classical NO signalling in these cells with low concentrations of GTN or 8-bromo-cGMP was also able to significantly (p < 0.05) reverse the hypoxia-mediated increase in MIF.
These results contribute to our understanding of MIF regulation, an important chemokine linked to cancer progression in numerous cancer sites. It appears that decreased NO signalling, as a result of microenvironmental hypoxia, is at least partially responsible for increased MIF secretion by cancer cells. These results justify further in vivo investigations of the role of nitric oxide signalling and MIF action and may represent a novel target for pharmacologic therapy for prostate cancer.
Engineered autologous urothelium (EAU) might be a treatment option for reconstructive urology. Clinical application requires compliance with legal regulations for media used for human urothelial cell (HUC) culture. The commonly used supplements cholera-toxin (CT), bovine pituitary extract (BPE), and fetal bovine serum (FBS) are not legally allowed. Native urothelium is a tight epithelium. The transepithelial resistance (TER) can therefore be used as indicator of epithelial differentiation and function in vitro. High TER is only reached in the presence of FBS. Aim of the study was to establish a cell culture medium for EAU suitable for an intended clinical application.introductory sentence or two indicating the objective of the study and its purpose.
Tested cell culture media were DMEM, DMEM/F12 (1:1), ker-atinocyte medium (KM) supplemented with CT, BPE, and human recombinant epidermal growth factor. TER measurements were performed in HUC cultures of 6 different cell lines at day 2, 7, and 9 after induction of stratification in the presence of 5% FBS. The expression of adherens junction protein E-Cadherin, tight junction protein ZO-1, and differentiation marker CK20 were analyzed immunologically.
In general, high variations between the TER in different HUC lines were observed. When DMEM and DMEM/F12 (1:1) were used as stratifying cell culture medium the mean values in the TER measurements revealed 3 to 4.5 times higher compared to the cultures when KM was used. The TER values within the DMEM group and the KM group were comparable. At day 2, 7, and 9 the DMEM group revealed mean values (Ohm·cm2) of 193 (±87), 2674 (±1977) and 3,638 (±3118), respectively. In contrast, the KM group showed 65 (±20), 847 (±1592) and 1,067 (±1304), respectively. TER reached higher levels in KM when CT and BPE were omitted. Stratifying HUCs cultured in DMEM-based medium revealed a higher CK20 expression and a homogenous distribution pattern of ZO-1 compared to a reduced CK20 expression and inhomogenous distribution pattern of ZO-1 in the KM group. E-Cadherin distribution was consistent in all groups.
TER, regarded as a sign for epithelial integrity, gives good evidence of tissue differentiation and function of bioartificial urothelial transplants when ZO-1 is homogenously distributed and TER is above 1000 Ohm·cm2. Furthermore, TER is an appropriate parameter for investigations on legally conform cell culture media for EAU. As the chemically defined DMEM and DMEM/F12 demonstrated better TER compared to KM, still FBS has to be substituted for legal conformance.
Bladder outlet obstruction (BOO) leads to overgrowth and remodeling of the detrusor. Strain, hypoxic injury and diabetic bladder models induce MMP7 expression which correlates with proliferation in many cell types. Regulation of MMP7 and FGF9 occurs in part through beta-catenin, GSK3-beta and mTOR, the mammalian target of rapamycin. Our purpose is to investigate the expression of beta-catenin target genes, MMP7 and FGF9, and their mTOR dependence during in vivo and in vitro bladder strain and hypoxia.
Sprague-Dawley rat bladders were partially (BOO) or sham (SHAM) obstructed for six-weeks (n = 4,3 respectively). In vitro, bladder smooth muscle cells (BSMC) were elongated 5% by slow ramping of static strain to mimic bladder distention in vivo. A humidified chamber was used at 1% or 3% O2 with 5% CO2 to simulate tissue hypoxia. BSMC were pretreated with rapamycin (10 ng/ml) at T = −1 hour. Real time PCR of MMP7 and other beta-catenin targets was performed on cDNA from in vivo and in vitro models by normalizing to gapdh or rpl32. Other MMPs (2,7,9,13) were examined by semi-quantitative PCR. Westerns for active beta-catenin were performed on the in vivo samples.
Of the MMP studied, MMP7 was significantly upregulated, 58-fold, during partial BOO (p < 0.05). FGF9 was increased 3-fold (p < 0.05). Other targets of beta-catenin (CCND1, EPHB3) showed increasing trends during BOO. Active beta-catenin showed a trend towards increasing, two-fold in BOO vs. SHAM bladders. In vivo, 5% stretch plus 1%O2 hypoxia increased MMP-7 expression, which was inhibited significantly by rapamycin (p < 0.05).
Transcriptional upregulation of beta-catenin target genes MMP-7 and FGF-9 implicates a role for this pathway during in vivo obstruction. Similar results in vitro suggest that application of stretch plus hypoxia mimics in vivo models. The ability of rapamycin to inhibit beta-catenin targeted growth-related genes provides another mechanism for the inhibition of growth of smooth muscle cells by this clinically approved drug.
The two signaling molecules that are extremely attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor γ (PPARγ). We evaluate the integration of combined drugs against these targets in the management of bladder cancer therapy.
The effect of EGFR inhibitor (Gefitinib) and PPARγ-agonist C-DIM, on cell growth, were screened in a panel of 9 human urothelial carcinoma cell lines derived from well-differentiated superficial bladder tumours as well as from high-grade invasive tumours. Cell proliferation was determined with an MTT assay after incubation with varying concentrations of the targeted agents (10−3 to 102 μM) for 72 hrs. Antiproliferative effects of combined therapy (Gefitinib and C-DIM) compared to each drug alone were monitored in vitro, by MTT assays, and in vivo, in nude mice inoculated with the more resistant cell lines (KU-7 and UM-UC13). Levels of expression of EGFR and PPARγ were evaluated by Western Blot analysis at baseline and after pre-treatment with EGFR inhibitor (Gefitinib). Immunofluorescence was then used to determine PPARγ nuclear accumulation mediated by Gefitinib. RT-PCR analysis was done to investigate expression of transcription factors involved in PPARγ induction
Gefitinib and C-DIM inhibit growth of bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. Induction of PPARγ expression was observed in response to different concentrations of Gefitinib for 24 h. Moreover, induction of PPARγ expression and nuclear accumulation was observed following EGFR inhibition through the transcription factor CCAT/enhancer-binding protein-β (CEBP- β). MTT assay shows that maximum inhibition of cell proliferation was observed when cells were pre-treated with Gefitinib for 24 h followed by C-DIM as compared to C-DIM followed by Gefitinib or each treatment alone. Tumour weight from mice treated with combined therapy was significantly lower than each treatment alone compared to control (p < 0.02).
Preliminary results suggest that PPARγ-agonist C-DIM can render bladder tumour sensitive to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.
Epinephrine is used to reduce surgical bleeding and improve visualization in various otolaryngological and neurosurgical operations. Transurethral resection of the prostate (TURP) remains the gold standard therapy for obstructive benign prostatic hyperplasia; however, visualization can be impaired by bleeding during the procedure. As a result, we investigate the use of intraprostatic epinephrine injection prior to TURP to reduce peri- and intraoperative bleeding.
Patients were randomized to receive either 20 cc of transurethrally injected intra-prostatic 1% lidocaine with 1:200,000 epinephrine or saline, in a double blind fashion. TURP followed immediately, using the modified Nesbit technique. Total blood loss, number of arteries requiring spot coagulation, resection time, visibility and safety parameters were recorded. All surgeries were performed by three urologists in a teaching environment. A priori total sample size was calculated to be 30 patients.
Fifteen (of a pre-planned sample size of 30) patients were randomized to either treatment group A (n = 8) or treatment group B (n = 7). The groups were similar with regards to age, BMI, prostate volume, indication for treatment and preoperative 5-alpha-reductase inhibitor and alpha-blocker usage. Mean blood loss was greater for treatment group A (44.9 ± 35.8 g) than for treatment group B (28.4 ± 19.8), albeit not significant, p = 0.33. The mean number of arteries requiring focal coagulation was not significantly different, at 8.5 (SD 3.7) for treatment group A and 8.0 (SD 3.2) for treatment group B, p = 0.786. There were no differences in mean resection time between treatment groups A (40.9 ± 14.1 min) and B (40.3 ± 17.4 min), p = 0.943 nor in the quality of visibility during resection (p = 0.322). Complications were rare, with no significant differences in cardiac arrhythmias nor changes in blood pressure in either treatment group, p = 0.876.
This is the first randomized clinical trial investigating the use of intraprostatic epinephrine pre-TURP. There is a trend to decreased blood loss for treatment group B, suggesting an emerging difference between treatment arms. This lack of statistical significance is likely an issue of power and sample size, which should be rectified at the final analysis.
Treatment of radio-recurrent current prostate cancer with curative intent is associated with significant morbidity. High intensity focused ultrasound (HIFU) is a relatively new treatment option that allows prostate ablation with minimal side effects in the primary setting, yet its morbidity in a salvage setting has never been compared to that of other minimally invasive treatments. We wished to examine whether salvage HIFU resulted in fewer complications than salvage cryotherapy (CRYO) in a single unit, single surgeon comparison.
Three cohorts of 47 patients were taken for this study. The first cohort consisted of the first 47 patients treated at our institution with CRYO to the prostate gland for radio-recurrent prostate cancer (1995–1998).The second cohort were the last 47 patients treated with CRYO between 2002 and 2004 (after 140 case had been performed) and our third cohort was the first 47 patients treated with salvage HIFU (2006–2009). Preoperative and postoperative morbidity data was recorded prospectively and compared for variations in morbidity.
Salvage HIFU treatment had lower rates of mild/moderate incontinence and urinary retention as well as lower rates of perineal pain. HIFU was associated with a similar rate of worsening of lower urinary tract symptoms (LUTS) and gross haematuria when compared with our initial experience with CRYO. With experience, LUTS reduced following CRYO. Recto-Urethral fistula rates low at 2%, 2% and 4% respectively. Results are summarized in Table 1.
|HIFU (n = 47)||Cryotherapy group 1 1995–1998 (n = 47)||Cryotherapy group2 2002–2004 (n = 47)|
|Patient age||68||67||p > 0.05||71.5||p > 0.05|
|Pre-salvage PSA||3.2||9.6||p < 0.001*||3.4||p > 0.05*|
|Mild/moderate incontinence||2 (4.3%)||23(49%)||p < 0.001||14 (30%)||p < 0.001|
|Severe incontinence||0 (0%)||0 (0%)||p > 0.05||1 (2.1%)||p > 0.05|
|Perineal pain||3 (6.4%)||10 (21%)||p > 0.05||7 (15%)||p > 0.05|
|Fistula||2 (4.3%)||1 (2.1%)||p > 0.05||1 (2.1%)||p > 0.05|
|Urinary retention||3 (6.4%)||15(32%)||p < 0.001||9 (19%)||p < 0.05|
|Gross hematuria||7 (15%)||6 (13%)||p > 0.05||3 (6.4%)||p < 0.05|
|Urethral sloughing||0 (0%)||2 (4.3%)||p > 0.05||6 (13%)||p < 0.05|
|Bladder neck contracture||0 (0%)||5 (11%)||p < 0.05||1 (2.1%)||p > 0.05|
|Urinary tract infection||4 (8.6%)||5 (11%)||p > 0.05||2 (4.3%)||p > 0.05|
|Worsening LUTS||22 (47%)||24 (51%)||p > 0.05*||13 (28%)||p < 0.05*|
Salvage HIFU was associated with lower rates of incontinence, perineal pain and bladder neck contracture than Salvage CRYO. Complication rates reduced with experience with CRYO with worsening LUTS being statistically significant; however, HIFU still compares favorably to even our most experienced CRYO results. This study confirms that salvage HIFU is a feasible salvage procedure with acceptable morbidity rates at least equivalent to salvage CRYO.
Secondary procedure rates of surgical therapy for BPH range between 1 and 14%. We evaluate GreenLight HPS™ laser PVP as a treatment for symptomatic BPH previously treated with surgical management.
We prospectively evaluated our initial GreenLight HPS™ laser PVP experience. Only patients who failed prior surgical therapy (transurethral prostate resection (TURP), transurethral microwave therapy (TUMT), holmium laser ablation of prostate (HoLAP) and potassium-titanyl-phosphate (KTP) laser PVP) for symptomatic BPH were included. Transurethral PVP was performed using a GreenLight HPS™ side-firing laser system.
Prior surgical management included TURP (18), TUMT (9), KTP laser PVP (8), HoLAP (2), TUMT and TURP (1), and TUMT and KTP laser PVP (1) in 39 of 181 consecutive patients. Mean prostate volume was 80.8 ± 50.0 mL. Mean laser and operative times and energy usage were 12.5 ± 10.5 minutes, 30.0 ± 24.0 minutes and 83.2 ± 64.4 kJ, respectively. Five patients developed a urinary tract infection. There were 36 patients who had nonsignificant hematuria for less than one week. Three patients had persistent urinary retention requiring clean intermittent catheterization. No urethral strictures or urinary incontinence were noted. All patients were able to discontinue their prostate medications following surgery. Mean American Urological Symptom Association Score (AUASS) decreased significantly from 22.8 to 8.2, 6.5, 6.5, 5.5, 4.6, 3.6 and 4.6 (p < 0.05) at 1 and 4 weeks and 3, 6, 12, 18 and 24 months, respectively. Mean maximum flow rate (Qmax) and post void residual (PVR) measurements also showed significant improvement from baseline. The incidence of adverse events were low.
Our initial results demonstrate that GreenLight HPS™ laser PVP is safe and effective for the treatment of symptomatic BPH recurring following prior surgical management.
|Pre Op||1 wk||4 wk||3 mo||6 mo||12 mo||18 mo||24 mo|
|Mean AUASS||22.8 ± 5.9||8.2 ± 5.1*||6.5 ± 3.6*||6.5 ± 5.3*||5.5 ± 2.5*||4.6 ± 2.7*||3.6 ± 2.0*||4.6 ± 2.7*|
|Mean QoL score||4.7 ± 1.1||1.4 ± 1.4*||1.0 ± 1.3*||0.9 ± 1.1*||0.8 ± 0.8*||0.6 ± 0.6*||0.3 ± 0.5*||0.7 ± 0.7*|
|Mean Qmax (mL/sec)||9.9 ± 4.0||18.4 ± 7.4*||20.6 ± 9.2*||20.9 ± 7.1*||19.7 ± 9.4*||20.8 ± 7.6*||23.2 ± 12.5*||18.3 ± 3.0*|
|Mean PVR (mL)||74.6 ± 94.3||47.7 ± 94.3*||47.6 ± 85.6*||41.5 ± 61.5*||42.7 ± 44.9*||39.0 ± 42.3*||38.3 ± 42.0*||41.0 ± 35.8*|
|N *p < 0.05||39||39||35||32||26||22||14||9|
We evaluate the efficacy and safety of GreenLight HPS™ laser PVP for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) with bilobe and trilobe prostates.
We prospectively evaluated our GreenLight HPS™ laser PVP experience. Based on the results of cystoscopy and transrectal ultrasonography, patients were stratified into two groups: bilobe (group I) and trilobe (group II) BPH. Transurethral PVP was performed using a 120W GreenLight HPS™ side-firing laser system. American Urological Association Symptom Score (AUASS), Quality of Life (QoL) score, maximum flow rate (Qmax) and post void residual (PVR) were measured preoperatively and at 1 and 4 weeks and 3, 6, 12, 18 and 24 months postoperatively.
There were 181 consecutive patients identified (l: 101, ll: 80). Among the preoperative parameters, there were significant differences in prostate volume (I: 46.5 ± 17.9, II: 97.5 ± 120.2 mL, p < 0.001.), Qmax (I: 10.1 ± 4.2, II: 8.7 ± 3.5 mL/sec, p = 0.027) and PVR (I: 60.4 ± 118.8, II: 97.5 ± 154.3 mL, p = 0.074), while AUASS (I: 22.7 ± 6.0, II: 23.0 ± 6.4, p = 0.695) and QoL (l: 4.7 ± 1.0, ll: 4.5 ± 1.1, p = 0.088) were similar. Significant differences in laser utilization (I: 8.9 ± 4.5 II: 19.5 ± 11.7 minutes, p < 0.001) and energy usage (I: 59.1 ± 30.0, II: 131.2 ± 79.6 kJ, p < 0.001) were noted. Clinical outcomes (AUASS, QoL, Qmax and PVR) were significantly improved post surgery within each group. AUASS, QoL and Qmax showed immediate and stable improvement during the follow-up period. There were no significant differences in the postoperative clinical outcome parameters between the two groups (p > 0.05). The incidences of adverse events were low in both groups.
Our experience suggests that BPH configuration has little effect on the efficacy and safety of GreenLight HPS™ laser PVP.
Hemoglobin is the primary chromophore of the potassium-titanyl phosphate (KTP) laser. It is postulated that the efficiency of the GreenLight HPS™ laser PVP in patients on long-term 5ARI, which reduce angiogenesis in benign prostatic tissue, may be decreased. We evaluate GreenLight HPS™ laser PVP as treatment for benign prostatic hyperplasia (BPH) in patients on long-term 5ARI.
We prospectively evaluated our initial GreenLight HPS™ laser PVP experience in patients with (5ARI+) and without (5ARI-) long-term 5ARI. Transurethral PVP was performed using a GreenLight HPS™ side-firing laser system with normal saline irrigant. Voiding trials were performed two hours post surgery. American Urological Association Symptom Score (AUASS), Quality of Life (QoL) score, maximum flow rate (Qmax) and post void residual (PVR) were measured preoperatively and at 1 and 4 weeks and 3, 26, 12, 18 and 24 months post surgery. Serum PSA and TRUS were also obtained at the 12 week follow-up interval.
There were 181 consecutive patients identified; 57 in 5ARI+ were on either finasteride or dutasteride and 124 in 5ARI- were not. Mean prostate volumes were 67.1 ± 35.3 and 69.2 ± 41.9 mL (p = 0.646) and mean PSA values were 2.2 ± 2.4 and 2.7 ± 2.6 ng/mL (p = 0.289), respectively. There were no significant differences in the parameters of laser utilization (13.6 ± 9.2 vs. 13.4 ± 10.4 minutes, p = 0.965) and energy usage (87.1 ± 62.4 vs. 91.8 ± 69.6 kJ, p = 0.623). All were out-patient procedures with the majority of the patients catheter-free at discharge. All patients were able to discontinue their prostate medications following surgery. The mean rates of prostate vaporization (2.7 ± 1.3 vs. 3.6 ± 2.4 mL/min, p = 0.08; 0.61 ± 0.81 vs. 0.53 ± 0.36 mL/kJ, p = 0.47) and TRUS volume 12 weeks post surgery (34.5 ± 27.1 vs. 36.8 ± 21.3 mL, p = 0.665) were similar between the two groups. Compared to baseline, PVR values decreased significantly in the 5ARI+ group (p < 0.05) but not in 5ARI- group. AUASS, QoL and Qmax values showed immediate and significant improvement from baseline (p < 0.05). AUASS, QoL, Qmax and PVR values at every time point showed no significant difference (p > 0.05) between the two groups during the follow-up interval. The incidence of adverse events was low and similar between both groups.
Our findings suggest that 5ARI do not have a detrimental effect on the efficiency and efficacy of GreenLight HPS™ laser PVP.
A redundant publication occurs when the same author or group of authors publishes a partial or complete duplicate of the scientific data from an existing manuscript. The steady push for academic and career advancement within the medical community can lead to a culture of “publish or perish”. Unfortunately this may result in redundant publications that erode the value and quality of academic literature. Our objective was to sample the extent and features of redundancy within the urological literature.
A review of all original index articles published in the Journal of Urology in 2006 was conducted using the PUBMED search engine. Editorials, reviews, urological surveys, and letters to the editor were excluded. Suspected redundant publications were identified by combining the last names of the first, second and last authors with the key words provided by the original article. Search results were limited to 2004–2008. Two senior investigators, each blind to the other, reviewed the suspected redundant publications and classified them as duplicate (identical materials, methods, results and conclusions), probable duplicate (almost identical materials, methods, results and conclusions), and salami-slicing (portions of index article repeated or continued). Discrepant classifications were resolved by mutual review and consensus.
From a total of 723 original index articles, 28 were identified to have 31 suspected redundant publications. Review of full text versions of the suspected redundant publications resulted in one (0.1%) article being classified as a complete duplicate, 6 (0.8%) articles as probable duplicates, and 5 (.7%) articles as salami-sliced. Therefore 12/723 (1.7%) of index articles were found to have some form of redundancy. The proportion of redundant articles published prior to, and following their index article was 7/12 (58.3%) and 4/12 (33.3%), respectively. One redundant article (8.3%) was published in the same month as its index article.
The detection of redundant publications is a difficult and laborious process for peer reviewers and editors. This sampling of the Journal of Urology suggests that the duplication rate in the field of urology is small but significant and appears to be similar to other surgical subspecialties. Further assessment of other Urological journals is warranted.
Inactivity is associated with increased morbidity and coagulopathy after major surgery. After radical prostatectomy, ambulation typically commences the morning of postoperative day (POD) 1. Some centres employ routine pharmacologic deep venous thrombosis (DVT) and pulmonary embolism (PE) prophylaxis, often starting therapy prior to intubation. We review our initial RALP experience in which patients routinely ambulate hours after surgery, focusing on how our patients fare with respect to the incidence of DVT and PE.
Consecutive patients undergoing transperitoneal RALP by a single surgeon (CW) were prospectively evaluated. Preoperative ted stockings and sequential compression devices (SCD) were provided in the ambulatory surgery unit. Following RALP and transfer from the post-surgical recovery room to a regular surgical ward, patients were instructed to ambulate with assistance twice before bedtime the day of surgery. Normal ambulation without assistance resumed POD 1. Pharmacologic anti-thrombotic therapy was not administered routinely before, during or after surgery unless requested by a consulting physician. Rates of common complications associated with immobility were examined.
There were 161 patients identified, having a mean age of 62.0 ± 8.1 years, an ASA of 2.2 ± 0.5 and 28.3 ± 3.9 kg/m2. The mean operating room time was 213.0 ± 54.0 minutes and mean hospitalization was 1.2 ± 1.0 days. The median urethral catheter duration was 5.0 ± 3.9 days. Adverse events included 1 fascial dehiscence, 2 (0.6%) DVT and 0 (0.0%) with PE. Anti-platelet therapy was withheld 10 days prior to surgery in one of the DVT patients.
Routine pharmacologic therapy to prevent perioperative thromboembolic events adds to hospitalization costs at a minimum. These results suggest that prophylactic pharmacologic intervention may not be required for DVT and PE prophylaxis when ted stockings, SCDs and early ambulation are employed.
Magnetic resonance spectroscopic imaging (MRSI) is now widely used as a tool for mapping key biomarkers in the prostate. In this work we present a novel MRSI technique, which identifies short echo time metabolites and improves the clinical usability of MRSI.
Subjects with prostate cancer were scanned on a GE 1.5T MR scanner using a standard endorectal coil in combination with a torso phased-array coil. MRSI data was obtained using a newly optimized pulse sequence (CV-MRSI) in addition to a set of T2-weighted fast spin echo (FSE) images. MRSI scans at long (130 ms) and short (40 ms) echo times (TE) were acquired using the standard, and novel technique. Each 3D MRSI acquisition used a 16x8x8 phase encode matrix, with a voxel size of 0.42 cm3. Preoperative biopsy was done using transrectal ultrasound. Following radical prostatectomy, the prostate was prepared for histopathological analysis. Spectra from voxels corresponding to malignant and normal tissue were analyzed using a modified version of LCModel.
A continuous improvement in data collection was observed when obtaining data from consecutive acquisitions. The spectra and LCModel fits obtained from the same voxels from long and short TE acquisitions. Comparing the spectra obtained at TE = 130 ms to that obtained at TE = 40 ms, we are observing on average 60% reduction in contaminating lipids, and significant improvement in the signal to noise ratio (SNR). As well, the citrate multiplet structure is clearly resolved. In addition we are also detecting several other short TE metabolites, such as taurine (Ta), inositol (In), and glutamate/glutamine (Glx) previously not observed.
MRSI can help decrease problems seen with conventional prostatic biopsy, such as sampling error. In this study, we have shown the efficacy of using a conformal voxel technique for the detection of short TE metabolites, while improving the SNR. This has enhanced the diagnostic quality of spectra throughout the prostate and improved the clinical role of spectroscopic imaging data, which is supported by post-prostatectomy histopathology.
Ultrasound procedures and transmission gel have been implicated in the spread of several bacterial pathogens including Burkholderia Cepacia. One of the authors (JH) has published a description of trans-rectal biopsy of the prostate leading to prostate infections with Burkholderia cepacia, secondary to intrinsically contaminated ultrasound gel. That paper focused on the microbiologic and infection control aspects of the outbreak. In this report we describe in more detail the clinical aspects of 6 patients who had a biopsy of the prostate resulting in acute and chronic infection with B. cepacia including therapy and outcomes. Included is the first report of chronic prostatitis caused by B. cepacia.
Patients who underwent trans-rectal biopsy of the prostate between 2000 and 2002 in Halifax, Nova Scotia and St. John’s, Newfoundland and subsequently were shown to have an infection with B. cepacia were reviewed retrospectively. Clinical and laboratory data was collected by retrospective chart review.
Contaminated ultrasound gel in this case was an unrecognized source of infection. During the time these infections occurred, ultrasound gel was purchased in large 4 to 5 L bottles and distributed to smaller refillable 250 ml to 1 L squeeze bottles. Therapy may be difficult for B. cepacia prostatitis. They sometimes required multiple IV antibiotics early in treatment to resolve symptoms. In particular, chronic prostate infection with B. cepacia, which has not been previously described in the literature, may be difficult to treat and resolve.
This series illustrates the importance of sterile technique and also sterile ultrasound gel. Although the rectal mucosa is involved and considered not to be sterile, these infections demonstrate how harmful organisms can still be transmitted to the patient during a TRUS biopsy. Single sterile packets of ultrasound gel should be used and refilling of containers should be banned. Attention should be taken to follow the manufacturer’s recommendations regarding device reprocessing to ensure proper cleaning and disinfection. After these changes were made in St. John’s and Halifax there were no further urinary tract infections with B. cepacia.
Chronic radiation cystitis is a difficult clinical problem leading to significant patient morbidity. Treatment of this disorder is poorly defined and generally ineffective. In the normal bladder, hyaluronic acid is theorized to function as a protective barrier aiding the repair of damaged mucosa. Intravesical instillation of hyaluronic acid is a recognized treatment for interstitial cystitis and thus a potential agent for treatment of Radiation induced cystitis.
A retrospective chart review was performed assessing all patients at a single centre treated with hyaluronic acid for exacerbations of chronic radiation cystitis between 2006 and 2009. Symptoms of this disorder can be quantified by the Radiation Therapy Oncology Group (RTOG) score for genitourinary radiation toxicity. This scale measures symptomatology on a grade of 1 (minor) to 5 (major). RTOG scores were assigned to patients with post radiotherapy cystitis before and after a treatment course with hyaluronic acid (Cystistat).
Eleven patients were identified who met such criteria. RTOG measurements for patients were an average of 2.9 (2–4) prior to hyaluronic acid instillation. After intravesical therapy with hyaluronic acid, the average RTOG toxicity score decreased to 1.6 (0–4). Eight patients (8/12) had improvement in their symptoms, 3 had stable symptoms, and only one patient showed worsening symptoms.
Hyaluronic acid instillations for radiation induced cystitis show promising preliminary results in this retrospective review. Further verification of its efficacy with prospective, randomized controlled trials is warranted.
Vasectomy is a simple, effective and commonly used method of contraception. In the United States, vasectomy is used by 11% of married couples and performed on approximately 500,000 men annually. Vasectomy is the most common urologic procedure performed today with an estimated 2–3% complication rate. Despite this low complication rate, vasectomy is the most litigated urological procedure. The complication of scrotal pain is very concerning to patients although there are only a few papers published on this topic. The true incidence of post-vasectomy scrotal pain is unknown, but estimates range from 0.9–33%. Our retrospective study examines the overall complication rate of vasectomies and specifically the incidence of scrotal pain.
A retrospective analysis was performed on patients who presented to a single urologist regarding possible vasovasostomy between March 1997 and January 2009. The vasectomies had been performed by a variety of physicians without a standardized technique. Patients with pre-existing testicular pain were excluded. Data regarding complications of vasectomy, specifically the incidence and duration of chronic scrotal pain were collected.
A total of 313 patients were identified and reviewed. The mean time from vasectomy to consultation was 102 months (range 10–432 months). The complication rate for hematoma, epididymitis, wound infection, hydrocele and failure was 8.6%. The incidence of post-vasectomy scrotal pain was 9.6% (n = 30). Of the 30 patients with post-vasectomy scrotal pain, 18 (60%) had occasional discomfort, 6 (20%) had post-coital pain, and 6 (20%) had chronic pain. Only 5 (17%) of the 30 patients with scrotal pain had a complication of their vasectomy. The pain eventually resolved in 6 (20%) of the patients.
Most of the literature surrounding vasectomy complications comes from experienced centres and they estimate the risk at 2–3%. It has been previously shown that physician experience is the single most important factor relating to complications. Our data shows a higher complication rate of 8.6% possibly because it represents a variety of physician experience and non-standardized technique. We found the incidence of post-vasectomy scrotal pain to be 9.6%. Most of these patients (60%) had occasional discomfort. Further study investigating the incidence and natural history of post-vasectomy scrotal pain with standardized questionnaires is necessary to better understand this complication.
There are few data on how often or how effectively clinical trial results are communicated to research study participants. We formally examined this issue in a survey which we administered to participants in an observational clinical study who were invited to an end-of-study presentation of study results.
We invited all participants of a longitudinal matched cohort study examining health effects of androgen deprivation therapy in older men with prostate cancer who were attending an end-of-study presentation to participate in our survey. Survey questions explored sociodemographic information as well as helpfulness of study results presentation, attitudes toward communication of study results, prior participation in clinical research, methods of communicating end-of-study results, and potential usefulness to others of study participation.
|Participants completing the survey (n = 59)||Study Participants 68%||Spouse 10%||Other Guest 22%|
|Was the study presentation informative?||Very informative/Informative 87.5%||Not Informative 12.5%|
|As a participant of a clinical research study do you have the right to be informed about study results when they are available?||Strongly agree/ Agree 85%||Neutral/ Not applicable 15%||Disagree 0%|
|If you had participated in any other research, were you invited for presentation or received study results?||Yes 14%||No 86%|
|How do you prefer to receive study results?||Email 46%||Presentation 45%||Individual meeting with study personnel 9%|
|Would you be more/less likely to participate in a study, where you know you would be provided with the results?||More likely/ Likely 90%||Neutral 9%||Less likely/ Lot less likely 2%|
|Are you satisfied with the way result were provided to you today?||Very satisfied/Satisfied 100%||Not Satisfied 0%|
|Best person to communicate study results?||Study Investigator 74%||Family physician 12%||Specialist/ Consultant 14%|
|Do you think this study and presentation benefit other patients?||Very likely/ Likely 91%||Neutral 7%||Unlikely 2%|
There were 59 of 70 presentation attendees (84%) who returned usable surveys. Thirty-nine (39) of 59 survey respondents were study participants while the rest were spouses or other guests; 71% of respondents were 65 years or older, 81% had completed at least some college or university, and 91% were either satisfied or very satisfied with participating in the study. Thirty-three percent of them had participated in clinical research before. Other key survey responses are summarized in Table 1.
The vast majority of participants in our study clearly wanted major end-of-study results made available to them, with equal numbers desiring an e-mail summary or a group presentation. Most expected this to come from the study’s principal investigator. Yet this seems to be happening uncommonly. An additional advantage of ensuring at the outset that such a presentation will occur may be to enhance participant recruitment and retention by gaining their trust, particularly in studies without many direct personal benefits to participants.
The genitourinary (GU) oncology division at Princess Margaret Hospital (PMH) has developed a site-specific BioBank to serve as a central repository for biospecimens obtained from patients attending out-patient clinics within the division. The GU BioBank was built to support research activities within the institution and beyond in a collaborative and accountable manner.
All consenting patients at high-risk for, or with bladder, kidney, prostate, and testis cancers (the Cohorts) agree to provide specimens prior to, during and following their treatment(s). Each sample collection point (Clinical State) is dictated by detailed flow diagrams developed for each disease cohort. We have developed the following number of clinical states for each disease cohort: Prostate (14), Kidney (11), Bladder (7), Testis (11). All blood and urine specimens are processed and stored by our collaborators at the Ontario Cancer Biomarker Network (OCBN). The specimens are catalogued, centrifuged, aliquoted, bar-coded, and stored in liquid nitrogen. Relevant clinical databases within the division are used for clinical outcomes determination. The GU Site group committee approves protocols and distributes samples to requesting investigators (following Research Ethics Board approval). The hierarchy for sample use gives precedence to those performing in-house academic projects, followed by collaborative academic projects, and lastly for commercial projects.
Since the date of its inauguration in May 2008, over 3000 patients have been recruited to the GU BioBank, and over 45,000 biospecimen aliquots have been stored. The GU Site BioBank continues to expand at a rate of 35 – 50 new participants per week, with a refusal rate of 7%. As of Jan 1 2010, the following number of specimen sets (one specimen set = all aliquots of plasma, serum, DNA and urine stored per patient per Clinical State) were available per disease cohort: Bladder (694); Prostate (2017); Kidney (329); Testicular (98); Other (133).
Focus to-date has been on producing a sufficient number of high quality specimens to enable statistically significant results in proposed studies. The GU BioBank has now reached this point for several Clinical States, and we have recently approved several research proposals requesting specimens from the BioBank. By enabling such research, we hope to facilitate the discovery of new diagnostic and prognostic biomarkers and achieve our ultimate goal of personalized medicine and improved outcome for GU oncology patients.
Bacillus Calmette-Guerin (BCG) is the treatment of choice for the management of high-risk non-muscle invasive bladder cancer. A large randomized controlled trial has shown that maintenance BCG improves recurrence-free survival and worsening-free survival. However, the 3-year maintenance BCG (SWOG) protocol, consisting of 27 installations, was shown to be associated with a very low completion rate of 16%, attributed largely to the side-effects of the treatment. We evaluated the rates of completion and reasons for premature treatment termination in our patients undergoing maintenance BCG with the SWOG protocol.
We evaluated 54 consecutive patients who were intended to receive a 3-year maintenance course of BCG at our institution between July 1 2003 and June 30 2009. Basic demographic data, treatment response, adherence to treatment and side effects were collected retrospectively. Moderate to severe side effects were defined as those that mandated discontinuation of therapy. Kaplan-Meier survival curves were employed to analyze survival data.
The mean age of the entire cohort was 67 years (range 49–89) and 42 (77.8%) patients were male. The median number of instillations was 21 (range 6–27). In total, 33 patients had a minimum of 3 years of follow-up allowing for completion of the maintenance protocol. Of these 33 patients, 15 (45%) completed the treatment without premature termination, 3 (9%) did not complete due to death of unrelated causes during the treatment. Four (12%) did not complete as they were lost to follow-up, 8 (24.2%) patients did not complete due to BCG failure, while only 3 (9%) patients prematurely terminated treatment due to side-effects. This is demonstrated in the freedom from interruptions due to side effects survival graph.
These results illustrate that contrary to previous findings, in a real-life clinical setting, side effects play a minor role (9%) in preventing patients from completing BCG maintenance therapy and that a significant number (45%) of patients are able complete the full course. Considering the well illustrated benefits of maintenance BCG, concerns of frequent and significant side effects should not deter clinicians from its use.
Meta-analyses of randomized trials indicate that overall survival is improved with the use of neoadjuvant chemotherapy (NAC) prior to cystectomy for muscle invasive urothelial carcinoma (UC) of the bladder. Typically perioperative cytotoxic regimens are selected based on objective response & survival benefits observed in the metastatic setting. HDI MVAC intensifies exposure to cisplatin & doxorubicin and shortens treatment time. In metastatic UC, HDI MVAC has a higher response rate (72%), lower neutropenia & mucositis rates, and superior survival compared to M-VAC (Sternberg 2006). These potential advantages led to its perioperative use at our institution & we report our results to date.
Patients (pts) receiving HDI MVAC as adjuvant or NAC for muscle-invasive UC were identified from institutional electronic databases. Pts with distant metastases were excluded. Chemotherapy was given as described by Sternberg (2001). Baseline, treatment & outcome data were extracted & analyzed.
Twenty eligible pts with muscle-invasive UC were identified with mean follow up of 12 mths (range 1.5–43.4). M:F 17:3, median age 56 (range 39–76), ECOG status 0:1:2 was 12:6:1. There were 101 cycles given with 2 pts still on treatment. Fifteen pts have completed treatment as planned (11 pts had 6 cycles & 4 pts had 4 cycles). Three pts stopped treatment after 4 cycles due to fatigue (2) or urosepsis (1). No toxic deaths were observed. Five pts had treatment delays & 2 pts had febrile neutropenia. Median survival to date is 8.1 mths (range 1.5–43.4). In the adjuvant group (n = 12), 10 pts had resected stage 4 disease: pT4aN2 (2 pts), pT4aN1 (4), pT3bN1 (2) & pT3aN1 (2) and 2 pts had pT3aN0. Seven adjuvant pts have had recurrence & 6 have died. All pts in the NAC group (n = 8) had cystectomy. Downstaging occurred in 5/6 evaluable pts and RECIST response was 5 PR & 1 SD. No pT0 was seen but 1 pt was pTaN0 and 4 were pT2N0. Three NAC pts have had recurrence & 2 have died.
This HDI MVAC cohort was younger and had high risk UC (74% pN+). Treatment was feasible & toxicity consistent with prior reports. Only 1 neoadjuvant pt had major response. HDI MVAC is a reasonable perioperative option for muscle invasive UC, but prognosis remains poor.
To determine how often patients who present to urologists with microscopic hematuria, and are investigated, are diagnosed with significant disease.
A retrospective chart review was performed of 248 consecutive patients who were referred with microscopic hematuria from January 2003, to December 2006. All patients included underwent full urologic work-up including, urinalysis, urine cytology, upper tract imaging, and cystoscopic examination.
The average age was 60 years. These included 123 females and 125 males, with average ages of 61 and, 59 years respectively. Urologic malignancy was detected in four patients, one female and three males. All patients with malignancy were over the age of 60 and, all were smokers. Three of the patients were diagnosed with Ta lesions, of these, one had atypical cytology. One patient was diagnosed with T1G3 with CIS, with cytology showing TCC. This makes for an overall detection rate of 1.61%.
In this population it is suggested that the presence of microscopic hematuria in smokers over the age of 60 can be associated with significant urologic pathology. In non-smokers under the age of 60 with microscopic hematuria investigation is extremely low yield.
Superficial bladder transitional cell carcinoma (TCC) requires adjuvant intravesical therapy to prevent recurrence and progression. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in most tumour cells. In partially TRAIL-resistant TCC cells, we have recently observed that gemcitabine and down-regulating Bcl2 with antisense oligodeoxynucleotide targeting Bcl2 (ASO-Bcl2) enhance apoptosis. These findings motivated us to further test the antitumour activity of TRAIL, combination of TRAIL with gemcitabine or ASO-Bcl2, in nude mice xenografted with human TCC cells.
Nude mice were either subcutaneously (s.c.) implanted with UMUC14 cells in their left flanks or orthotopically with Ku-7 cells in their bladders. When s.c. tumours reached ~3 mm in diameter, animals were treated with (a) TRAIL, intratumour injection (i.t.) or intraperitoneal injection (i.p.), 20 μg daily; (b) gemcitabine, i.p., 2 mg twice weekly; (c) saline (control), i.t.; for 6 injections per animal. At 4 days after Ku-7 cell instillation, animals were allocated to intravesical treatments: (a) TRAIL, 40 μl (20 μg) on day 4, 5, 6, 11, 12, 13; (b) TRAIL, plus gemcitabine (5 mg/ml) on day 7, 8, 14, 15, 19, 20; (c) TRAIL, plus ASO-Bcl2 (1000 μM) on day 7, 8, 14, 15, 19, 20; (d) saline control.
Based on cytotoxicity data, TCC cells were divided into sensitive or partially resistant to TRAIL or gemcitabine. UMUC14 cells were sensitive to TRAIL but partially resistant to gemcitabine, while Ku-7 cells were partially resistant to TRAIL. All 4 animals bearing s.c. UMUC14 tumours were cured by TRAIL i.t. and 2 of the 4 tumours were cured by gemcitabine i.p. No tumour was cured by TRAIL i.p. or saline i.t. For the orthotopic Ku-7 tumour model, the control group (6 mice) all had tumour with a median survival of 46 days. Other 3 groups (10 mice per group) received instillations of TRAIL, or TRAIL plus gemcitabine or ASO-Bcl2, attained a significant survival benefit over the controls with median survival of 95, 83 and 70 days, respectively. Tumour-free survivals were observed.
TRAIL can effectively control tumour growth when it is given i.t. or intravesically. Combination of TRAIL with gemcitabine or ASO-Bcl2 has not enhanced efficacy in vivo and needs further study.
Management of advanced renal cell carcinoma (RCC) and bladder transitional cell carcinoma (TCC) remains a clinical challenge. Improved understanding of cell biology has led to development and approval of several new agents with specific signaling targets. Nevertheless, questions remain about the optimal use of these agents and combination approaches. This study investigated the impact of tyrosine kinase inhibitors (TKIs: Sorafenib, Sunitinib), mammalian target of rapamycin (mTOR) inhibitor (mTORI: Temsirolimus) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on migration, invasion and proliferation of RCC and TCC cells.
RCC (786-O, ACHN, A498) and TCC (HT1376, UMUC14, T24, RT112, 253J, MGHU3) cells in logarithmic phase in appropriate media were tested. To assess drug cytotoxicity, TCC cells were exposed to varying concentrations of sorafenib, sunitinib or temsirolimus for 20 h followed by TRAIL or growth medium for additional 20 h, after which the proportion of viable cells was determined by MTT assay. Expression of apoptotic proteins was determined by Western blot analysis. To assess impact on invasion, RCC cells (in Matrigel chambers of 8-micron pores) were incubated with TKIs in media without FBS; using 10% FBS in the lower chamber media as chemo-attractant. After 40 hours of migration, the filter containing the adherent cells was stained with hematoxalin, imaged under microscope and counted using Metamorph software. A wound-healing scratch assay was used to assess the migration of RCC cells cultured with TKIs. Cells were incubated and allowed to migrate for ~24 h with time-lapse images captured by an axiovert microscope and analyzed using t-scratch software.
Sorafenib inhibited proliferation of TCC cells irrespective of TRAIL-sensitivity. The sorafenib induction or augmentation of TRAIL-apoptosis in TCC cells was accompanied by increased activation of proapoptotic proteins (XIAP, p53, procaspases 9, 8 and 3). Sunitinib and Temsirolimus did not enhance the anticancer effect of TRAIL. Compared with controls (100% invasion), the invasion of RCC cells was reduced to <10% by Sorafenib and 30–75% by Sunitinib. A time- and dose- dependent RCC migration inhibition by TKIs was observed. Sorafenib, a more pan TKI, had greater effect than Sunitinib.
Inhibition of the tyrosine kinase pathway using sorafenib (but not Sunitinib) potentiated TRAIL-induced lethality in TCC cells. TKIs also inhibit migration of RCC cells. This study provides valid rationale to use TKIs and TRAIL in neo-adjuvant therapy of RCC and TCC.
Local recurrences are relatively uncommon after radical cystectomy and patients with local recurrences are known to have poor prognosis. Local recurrence may potentially be avoidable with correct surgical techniques such as larger resection margins or extended lymph node dissection. Therefore, the study objective was to identify risk factors for isolated local recurrence for the purpose of avoiding these events in the future.
We studied a large retrospective RC database (n=601) including BC patients operated at the University Health Network, Toronto, Canada (n=351, study period 1992–2008) and University of Turku, Turku, Finland (n = 250, 1986–2005) with special attention to quality of the data. After excluding non-TCC tumours and patients without recurrence, we had a total of 181 patients. Isolated local recurrence was defined as tumour recurrence in the pelvis caudal to aortic bifurcation with no evidence of distant metastasis. Analyzed variables included gender, smoking, type of diversion, extent of node dissection (<15 nodes vs. ≥15 nodes removed), pT-stage, N-status, CIS, lymphovascular invasion, margin status and neoadjuvant/adjuvant chemotherapy. Correlation between recurrence type and clinicopathological variables was examined using univariate analysis, Kaplan-Meier survival method and cox regression multivariate analysis.
Of the 181 patients with recurrences, 37 had isolated local recurrence representing 20% of all recurrences and 7% of all TCC patients undergoing RC. The mean time to local recurrence was significantly shorter than to distant recurrence (10 vs. 19 months, p = 0.025) and the mean disease specific survival was 19 vs. 32 months for local and distant recurrence, respectively (p = 0.14). In a multivariate analysis, female gender was the only significant risk factor for local recurrences (HR 3.41, 95% CI 0.13–0.65, p-value = 0.003). The rates for isolated local recurrences in patients undergoing extended and limited node dissection were 15%, and 22%, respectively, but the difference was not significant (p = 0.29). Though positive bladder surgical margins were reported in 6% of all cases of recurrence, they had no correlation with local recurrence (p = 0.7) or gender (p = 0.3).
Surprisingly, female gender was significantly associated with risk of isolated recurrence. The reason for this observation remains speculative, but attention should be paid to surgical technique in females. There was also a trend for decreased local recurrences in patients receiving extended lymphadenectomy.
Muscle-invasive bladder cancer (BC) is an aggressive tumour with high risk of relapse after radical cystectomy (RC). As the role of perioperative chemotherapy after radical cystectomy is not well defined at the present time, we are in need of prognostic factors to determine patients at high risk of disease relapse. Our objective was to present combined results from two large series and to analyze our detailed database for variables associate with tumour relapse and poorer survival.
A large retrospective RC database including BC patients operated in University Health Network, Toronto, Canada (n = 351, study period 1992–12008) and University of Turku, Turku, Finland (250, 1986–2005) was studied. After excluding non-TCC tumours (n = 46), 555 patients were available for analysis. The relationship of gender, smoking, CIS, lymphovascular invasion (LVI), margin status, pT-stage, lymph node (LN) status, LN density (LND) and adjuvant chemotherapy to disease and overall specific mortality (DSS, OAS) was examined using univariate and multivariate analysis as well as Kaplan-Meier survivals and Cox regression analysis.
The mean FU was 4.0 years (median 2.3, range 0–20 years). The 5-y and 10-y DSS was 70%, and 69%, respectively. The 10-y DSS for pT1, pT2, pT3, and pT4 were 81%, 66%, 53%, and 39%, respectively. For ND- and ND+ patients the 10-y DSS was 76%, and 36%, respectively. For ND positive patients with LND <20% 10-y DSS was 43% compared to 29% in patients with LND <20%. In a multivariate analysis, factors associated with DSS were higher pT-stage, positive LN, and LVI (p <0.001, <0.001 and 0.002, respectively), and those associated with overall mortality were older age, higher pT-stage, positive LN and LVI (p 0.04, 0.001, <0.001 and 0.003, respectively). When the effect of LVI was studied in detail, it was significant risk factor for the whole cohort and ND negative patients (p < 0.000), but not in ND positive patients (p = 0.219).
Our results generally confirm the outcome reported in many previous series. RC offers high rates of survival in organ-confined and ND negative tumours. In addition to tumour stage and nodal status, LVI is significant risk factor for BC related death. Although ND metastasis is associated with significantly poorer survival, it should be emphasized that radical cystectomy offers long-term survival in approximately 1/3 of LN positive cases, which is similar to some previous reports which had been sometimes deemed too optimistic. In addition, LND with a cut-off of 20% offers further prognostic information for ND positive patients.
Smoking is a known carcinogenic associated with significant morbidity and health care costs. Although smoking is a documented risk factor for bladder cancer (BC), less is known about the natural history of tobacco-induced tumours compared to BC in non-smokers and whether it impacts presentation or outcome of muscle invasive BC. The objective of the study was to evaluate BC pathology and survival among smokers and non-smokers after radical cystectomy (RC).
A large retrospective RC database including BC patients operated at the University Health Network, Toronto, Canada (n = 351, study period 1992–2008) and University of Turku, Turku, Finland (n = 250, 1986–2005) was accrued. Patients with non-TCC tumours (n = 46) or unknown smoking status (n = 54) were excluded resulting in 501 patients for analysis. Smoking was defined as any documented history of smoking (both current and former smokers). Other variables included gender, age, tumour pT-stage, nodal status and adjuvant chemotherapy. Correlation between smoking and clinicopathological variables was examined using univariate analysis, Kaplan-Meier survival and cox regression multivariate analysis.
The study included 501 patients with a mean FU of 4.2 years (median 2.4, range 0–22); 78% were males and the mean age was 66 years; 35% had extravesical disease and the node metastasis rate was 20%; 320 (64%) patients had a documented history of smoking (48% reported to be current and 52% former smokers). Significant variables associated with smoking in univariate analysis included: male gender (p = 0.006), advanced pT-stage (p = 0.035), nodal metastasis (p < 0.000) and younger age (mean age 65 vs. 68 years, p = 0.002). All of these variables remained significant in a multivariate logistic regression analysis. With Kaplan-Meier analysis there was no difference in recurrence free survival (RFS) and disease specific survival (DSS) between smokers and non-smokers (log-rank p-value 0.33 and 0.43, respectively), while overall survival (OS) was significantly poorer among smokers (log-rank p-value 0.044). In multivariate Cox-regression analysis for DSS, higher pT-stage and positive nodes remained significantly associated with poorer outcome (p < 0.001, and 0.002, respectively).
Smokers present at an earlier age, with more advanced tumour stages and with increased frequency of nodal metastasis at the time of RC. Smoking is an independent predictor of OS but not DSS after RC. A possible reason for the discrepancy between more advanced tumours, but similar disease-specific survival is the presence of competing risk factors for death among smokers.
To examine cancer-specific mortality (CSM) in patients with pT4N0-3M0 urothelial carcinoma of the urinary bladder (UCUB) and to compare it to patients with pT3N0-3M0, in a population-based cohort treated with radical cystectomy (RC).
Radical cystectomies were performed in 5625 pT3-T4bN0-3M0 patients with UCUB within 17 Surveillance, Epidemiology and End Results (SEER) registries between 1988 and 2006. Univariable and multivariable models tested the effect of pT4a vs. pT4bvs. pT3 stages on CSM. Covariates consisted of age, gender, race, lymph node status and SEER registries. All analyses were repeated in 3635 N0 patients..
Of 5625 patients, 2043 (36.3%) had pT4aN0-3, 248 (4.4%) had pT4bN0-3 and 3334 had pT3N0-3 (59.3%) UCUB. The 5-year CSM was 57.6% vs. 81.7% vs. 53.9% for respectively pT4aN0-3 vs. pT4bN0-3 vs. pT3N0-3 patients (all log rank p = 0.008). In multivariable analyses the rate of CSM was 2.3-fold higher in pT4b vs. pT3 (p < 0.001), 1.1-fold higher in pT4a vs. pT3 (p = 0.002) and 2.0-fold higher in pT4a vs. pT4b patients. After restriction to pN stage, pT4b patients had a 2.3-fold higher rate of CSM than pT3 patients (p < 0.001) and a 2.1-fold higher rate in pT4a vs. pT4b (p < 0.001). The CSM rate was the same for pT4a and pT3 patients (p = 0.1).
Our findings indicate that pT4a patients have similar CSM as pT3 patients. In consequence, RC should be fully considered in that group.
Data on the role of HPV in bladder carcinogenesis are controversial. Dysregulation of p53 is critical in the development of TCC of urinary bladder. Few studies have documented concurrent HPV positivity and abnormal p53 accumulation in bladder TCC. Aims of our study were to assess frequency of p53 gene mutations, prevalence of HPV infection in patients with TCC of urinary bladder and to find out its correlation with standard clinical and histological parameters for tumour recurrence and progression.
Tumour tissue samples of 50 patients with transitional cell carcinoma (TCC) of urinary bladder obtained by TURBT or radical cystectomy were examined histopathologically. P53 mutations were assessed by DNA isolation and PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis. PCR (Polymerase Chain Reaction) was used to detect HPV DNA (type 16 & 18). Data were analyzed by Fisher’s two tailed t-test & Pearson’s chi-square test using SPSS 15 statistical software.
Twenty (40%) patients had presented with primary superficial tumours,12 (24%) with recurrent superficial and 18 (36%) had invasive TCC. 10% had Ta, 54% had T1 and 36% had T2 lesion. Out of 50 patients 7 (14%) had p53 mutations detected in exons 5 and 6. P53 mutations were more in invasive tumour (n = 4, 57.1%) as compared to superficial tumour (n = 3,42.9%). None of the 50 bladder cancer specimens were positive for HPV DNA.
HPV 16 & 18 prevalence is very low amongst Indian patients with bladder cancer and therefore unlikely to be the causative factor for bladder TCC. P53 mutations are associated with aggressive behavior. Therefore patients having tumour with p53 mutations should be followed up closely. This molecular prognosticator may play a role in the clinical routine management of patients with bladder tumour. Further studies should explore their potential clinical significance taking into their cost-effectiveness.
Urothelial carcinoma of the bladder is a common malignancy and a major cause of morbidity and mortality. Urinary cytology is the most widely used non-invasive test for its detection and surveillance. We aimed to re-evaluate the specificity of urine cytology during a contemporary period at our institution in comparison to other urinary biomarkers.
Data from 1,114 consecutive patients corresponding to 3,261 specimens (2,979 cytologic and 282 histologic specimens) between January 2006 and July 2006 were retrieved. Subsequent cytologic and surgical specimen reports up to 2008 were examined with a minimum two year follow-up period. Collected parameters included date of collection, reason for urinary evaluation, type of specimen (voided, washing or catherized) and tumour grade. Atypical diagnosis was considered negative.
On cytological examination, 71% of specimens were benign, 23% atypical and 6% suspicious or positive for urothelial carcinoma. The reason for collection was surveillance in 48%, new onset hematuria in 22% and other causes in the remaining cases. Depending on tumour grade, sensitivity results ranged from 11% for low-grade tumours to 49% for high-grade ones. Importantly, specificity of urine cytology ranged from 77% to 89% (depending on type of urine collection and type of clinical presentation), similar to other reported results from other urinary markers (40–90%).
Our institution’s experience with regards to the sensitivity of urine cytology is similar to other reports in the literature. However, the specificity of urine cytology is significantly lower than reported historically. These findings need to be validated in a larger cohort of patients across several institutions to definitively evaluate whether there remains an advantage for urine cytology over the other urinary marker assays
The Notch pathway plays a critical role in growth and differentiation, and is involved in cancer progression in different organ sites. Little is known about Notch in bladder cancer. In this study, we evaluated the expression of Notch receptors in a panel of bladder cancer cell lines.
Thirteen bladder cancer cell lines with previously described invasive properties and epithelial/mesenchymal characteristics were screened for expression of the Notch receptors by Western blot and real-time PCR. Immunohistochemistry (IHC) was performed on a tissue microarray (US Biomax, Inc., Rockville, MD) that included cores from 152 patients with bladder cancer. Alterations in gene expression after Notch-2 silencing with siRNA were measured by expression microarray in 3 cell lines. Genes that changed by at least 2-fold in all 3 cell lines were selected for further analysis. Wound healing assays were performed after treatment with Notch-2 siRNA versus scrambled siRNA. The Mann-Whitney test was performed for statistical analysis.
Epithelial cell lines with low invasive potential expressed Notch-1 at high and Notch-2 at low relative levels (p = 0.03 and p < 0.01, respectively) compared to invasive cell lines. Highly invasive, mesenchymal cell lines expressed high levels of Notch-2 and low levels of Notch-1. These results were validated by Western blot and IHC (TMA). Microarray analysis revealed altered expression of genes related to epithelial to mesenchymal transition (EMT), protein and endosome trafficking, and cell-cell connections, when Notch-2 was silenced with siRNA. Notch-2 silencing decreased the migration of UC3 cells in the wound healing assay (p = 0.02).
These results provide preliminary evidence for a role for Notch in the progression of bladder cancer and it is suggested that this may be related to EMT. Further investigation is needed to assess the suitability of Notch as a therapeutic target, and it would appear that selective inhibition of individual Notch receptors may be preferential to global inhibition.
MicroRNAs (miRNAs) are a class of small RNAs that are important regulatory molecules, involved in several cell processes such as developmental timing, stem cell division, and apoptosis. Dysregulated miRNAs have been identified in several human malignancies, including bladder cancer tissue samples, and may confer a “tumour signature” that can be exploited for diagnostic purposes. We report on a prospective pilot study investigating the diagnostic capability of miRNAs in the urine of patients with urothelial cancer.
Voided urine samples were collected from 8 patients with urothelial carcinoma just prior to bladder tumour resection as well as 5 age-matched healthy control patients. Pathology demonstrated both low grade and high-grade cancer. Total RNA was isolated and quantitative reverse transcriptase-polymerase chain reaction was performed on the RNA extracts using primers for 4 miRNAs shown previously to be dysregulated in solid urothelial carcinomas with RNU6B as the endogenous control. Standard urine cytology was performed on all samples in a blinded fashion.
Two miRNAs were found to be significantly dysregulated in the urine from cancer patients with miR-A showing an average 10.42-fold decrease (p < 0.05) and miR-B showing an average 2.70-fold increase (p > 0.05) in the cancer samples compared to the normal controls. Using these 2 miRNAs, a decision-tree prediction model was generated yielding a specificity of 100% and a sensitivity of 87.5%. The sensitivity and specificity of the cytology on the same urine samples was 50% and 80% respectively.
MiRNA expression levels are altered in bladder cancer and may have diagnostic and prognostic value. This preliminary study of candidate urinary miRNA in patients with both low grade and high-grade urothelial cancer demonstrated a significantly improved diagnostic accuracy over cytology. These results provide rationale for further studies on discovery and validation of candidate miRNAs in voided urine and may potentially lead to the development of a non-invasive and sensitive test for bladder cancer diagnosis and prognosis.
Recent literature indicates that continent urinary diversion (CD) is offered to a minority of patients after radical cystectomy (RC). An elevated rate of peri-operative complications may represent an explanation for this observation. We examined the rates of immediate inpatient complications for CD vs. incontinent urinary diversion (ID).
Between 2003 and 2008, 2719 RC were performed in the state of Florida. The type of diversion and complications were recorded within the Florida Inpatient Database. Statistical analyses assessed the overall and specific complication rates in patients with CD and ID after RC. Covariates consisted of age, gender, race, hospital volume (HV) and surgical volume (SV), as well as Charlson Comorbidity Index.
Between 2003 and 2008, the rate of complication after RC ranged from 9.2 to 10.5%. The overall complication rate after CD was 29.5% vs. 39.2% for ID (p < 0.02). In univariable models, younger age (OR: 1.02 [95% CI = 1.01–1.03]; p < 0.001); female gender (OR: 0.78 [95% CI = 0.63–0.96; p = 0.02) and CD (OR: 0.65 [95% CI = 0.49–0.86]; p = 0.003) were significant predictors of lower overall complication rates. In multivariable analyses, younger age (OR: 1.02 [95% CI = 0.66–1.22]; p < 0.001), female gender (OR: 0.72 [95% CI = 0.58–0.89]; p = 0.003); higher HV (OR: 1.93 [95% CI = 1.49–2.52] p < 0.001) and higher SV (OR:1.71 [95% CI = 1.25–2.31]; p < 0.001) remained independent predictors of lower complication rates. However, after adjustment for covariates, the type of diversion failed to predict any type of complications.
CD does not predispose to higher rates of complications. In consequence, CD should be encouraged whenever not medically contraindicated.
To assess the rate of metastatic bladder cancer at diagnosis in a population-based tumour registry.
Between 1988 and 2006, 29 381 patients were identified within 17 Surveillance, Epidemiology and End Results (SEER) registries with diagnosis of bladder cancer of all stages. We examined the rates of metastatic bladder cancer at diagnosis throughout the entire study period. Multivariable logistic regression models examined the impact of year of surgery on metastatic bladder cancer diagnosis after adjusting for patient age, gender and race.
The overall rate of metastatic bladder cancer was 7.1% and it increased from 6.3 to 8.4% over the study period (relative increase: 1.3%, χ2 trend: p < 0.001). The increase in metastatic bladder cancer rates was more pronounced in females (relative increase: 6.5%; from 1.4 to 9.1%, χ2 trend: p = 0.4) than in males (relative increase: 1.5%; from 5.2 to 7.6%, 2 trend: p < 0.001) and in octogenarians (relative increase: 1.2%; from 8.4 to 9.8%, χ2 trend: p = 0.7) than in younger patients (relative increase: 1.1%; from 7.9 to 8.7%, χ2 trend: p = 0.003) and in Caucasians (relative increase: 1.4%; from 6.0 to 8.3%, χ2 trend: p < 0.001) than in other race categories (relative increase: 1.0%; from 8.8 to 8.9%, χ2 trend: p = 0.8). Statistically significant differences in metastatic bladder cancer rates existed in various SEER registries. For example, the increase in metastatic rates was the highest in the Los Angeles and Utah registries (relative increase: 2.1%, from 6.1 to 12.6%, χ2 trend: p < 0.001 and relative increase: 2.4%, from 3.8 to 9.1%, χ2 trend: p = 0.01). In multivariable logistic regression models age, gender and race represented independent predictors of metastatic bladder cancer diagnosis (p ≤ 0.04). Finally, more contemporary year remained the foremost predictor of higher rate of metastatic bladder cancer at initial diagnosis (p < 0.001).
The increase in metastatic bladder cancer rate is worrisome. Delay at presentation as well as a delay in referrals may be the underlying cause behind these increasing rates. Although the increase in trends is marginal, it represents a cause for concern, which indicates that primary care physicians and patients should be better sensitized to the importance of expedited referrals and self diagnosis.
We sought to examine stage at radical cystectomy (RC), as well as cancer-specific mortality (CSM) rates in non-bilharzial squamous cell carcinoma (SCC) RC patients relative to patients with urothelial carcinoma (UC) RC of the urinary bladder within a large population-based cohort. We hypothesized that SCC histological subtype fares a worse survival than UC patients.
Of 12 311 RC cases, we identified 614 (5.0%) SCC versus 11 697 (95.0%) UC individuals within 17 Surveillance, Epidemiology, and End Results (SEER) registries between 1988 and 2006. Differences in the rates of CSM were assessed using the cumulative incidence plots that control for non-cancer related mortality. Univariable and multivariable competing-risks regression models addressed the effect of histological subtype at RC for prediction of CSM. Covariates consisted of age, gender, year of diagnosis, race, pathological T and N stages, as well as tumour grade.
After accounting for other-cause mortality, the cumulative CSM rates at 5 years were 40.3 and 35.1% for SCC vs. UC patients (p < 0.001, Gray). For the same time point, the CSM rates in organ confined (OC) disease were 25.0 and 19.8% for SCC vs. UC patients (p = 0.2, Gray) and 46.3 and 49.3% respectively for the same groups of patients in non-organ confined (NOC) disease (p = 0.8, Gray). In multivariable competing-risks regression models, SCC was not associated with a statistically significantly higher rate of CSM than UC histological subtype (p = 0.06, Gray). Similarly, SCC was unassociated with a higher risk of CSM after stratification according to OC and NOC disease (p = 0.2 and p = 0.1, Gray).
SCC is rare, and more frequently associated with non-organ confined disease. After accounting for non-cancer related mortality, which was never previously done with Cox regression models, SCC was not statistically significantly related to a worse prognosis than UC subtypes.
The radical cystectomy (RC) population is very heterogeneous with respect of cancer-specific (CSM) and other-cause mortality (OCM). Comorbidities and comorbidities-associated events represent very important causes of mortality in RC patients. We examined the rates of CSM and OCM in a population-based RC cohort.
We identified 11 260 patients treated with RC for urothelial carcinoma of the urinary bladder between 1988 and 2006 within 17 Surveillance, Epidemiology and End Results database. Patients were stratified into 20 age-tumour stage categories. Poisson regression models were fitted to obtain estimates of CSM and OCM mortality rates at specific time points after RC.
After stratification according to disease stage and patient age, CSM resulted as the main cause of mortality in all patients strata. Nonetheless, at 5 years after RC between 8.5 and 27.1% of deaths were attributable to OCM. The three most common causes of OCM were heart disease, other malignancies and chronic obstructive pulmonary disease. The most prominent effect on CSM was exerted by locally-advanced BCa stages. Conversely, age was the main determinant of OCM. Interestingly, even after adjusting for bladder cancer pathologic stage, CSM was higher in older individuals than in younger patients.
Our model represents a valuable tool capable of predicting OCM and CSM according to disease stage and patient age. The model results can help clinicians to better stratify the risk-benefit ratio of RC. Hopefully, this tool will be integrated into patient counseling and informed consent process prior to RC in patients who represent surgical candidates.
Prognostic significance of advanced age on cancer-specific mortality (CSM) following radical cystectomy (RC) remains controversial. Previous data demonstrated that advanced age predisposed to an increase in CSM, but in other studies it had no effect. However, in those reports, other-cause mortality (OCM), which may affect the rates of CSM, was unaccounted for. To further refine the existing analyses, we attempted to assess the effect of advanced age on CSM after RC within a large population-based cohort using competing-risks regression models.
Using the Surveillance, Epidemiology, and End Results (SEER)-17 database, we identified 11 854 patients who were treated with RC for transitional cell carcinoma of the BCa. Age was stratified into four decades: ≤59 years old, 60–69 years old, 70–79 years old, and ≥80 years old. Univariable and multivariable logistic regression models examined the effect of age on T and N stages at RC. Subsequently, cumulative incidence plots explored the impact of age on CSM rates, after accounting for OCM. Finally, competing-risks regression models tested the independent predictor status of age in CSM analyses.
In multivariable logistic regression models, increasing age achieved independent predictor status (60–69: OR = 1.07, 95% CI = 0.96–1.18, ≥80: OR = 1.29, 95% CI = 1.12–1.47, p < 0.001). After controlling for OCM, the cumulative CSM rates at five years for age categories ≤59, 60–69, 70–79 and ≥80 years were respectively 31.6% vs. 35.1% vs. 35.6% vs. 43.6% (p ≤ 0.001, Gray). In multivariable competing-risks regression analyses, increasing age achieved an independent predictor status of CSM (60–69: HR = 1.13, 95% CI = 1.04–1.24, ≥80: HR = 1.62, 95% CI = 1.44–1.82, p ≤ 0.007).
Advanced age at RC for transitional cell carcinoma of the BCa is independently associated with significantly different outcomes, even after adjusting for the possibly confounding effect of OCM. This may imply that older patients are treated less readily with RC than their younger counterparts.
Several coding schemes have been proposed to best define the prognostic value of nodal status at radical cystectomy, namely lymph node density, number of positive nodes, number of removed nodes, and pathologic N-substages of the TNM classification. We compared the prognostic ability of these definitions for the prediction cancer-specific mortality (CSM).
Between 1988 and 2006, 7624 assessable patients underwent radical cystectomy and pelvic lymphadenectomy within 17 Surveillance, Epidemiology, and End Results registries. Univariable and multivariable Cox regression analyses addressed the prognostic impact of different nodal status coding schemes on CSM after surgery. Covariates consisted of age, gender, T stage and tumour grade. Harrell’s concordance index quantified accuracy and 200 bootstrap resamples were used to correct for overfit bias.
In multivariable analyses addressing CSM after surgery, nodal stage, regardless of its coding, achieved the independent predictor status (p < 0.001). Lymph node density represented the most informative predictor of CSM in the entire cohort (gain in predictive accuracy: 2.6%), followed by pN-substages (gain in predictive accuracy: 2.5%) and by the lymph-node density categorized in ≤20% and >20% (gain in predictive accuracy: 2.3%). However, the differences in predictive accuracy between the three coding schemes were not statistically significant.
Although several nodal coding schemes may appear conceptually attractive, from a prognostic perspective the pathologic N-substages perform well and represent a nodal coding scheme that all clinicians are familiar with.
Primary radiation therapy (RT) for bladder cancer has yet to establish itself as a common treatment in Canada and the USA. Several centres have shown encouraging results with a multimodal organ-sparing approach that compares favourably to radical cystectomy. The published reports emphasize the requirement for the combination of complete tumour resection (TURBT), chemotherapy and RT. As with many aspect of bladder cancer management, it is unclear to what extent these guidelines are being followed. The aim of this study was to identify retrospectively the practice patterns in British Columbia for patients with bladder cancer who receive primary RT.
All patients undergoing radical cystoprostatectomy or primary RT between 1988 and 2007 were selected from the registry of the British Columbia Cancer Agency. Key demographic and clinical parameters were reviewed retrospectively.
The mean age of patients receiving primary RT (n = 624) versus cystectomy (n = 571) was 75.0 versus 66.7 (P = 0.05) respectively. The majority of patients in both groups were clinical stage T2 (33.3% for RT and 16.7% for cystectomy). For patients receiving RT, 28.8% went on to have salvage cystectomy, indicating that treatment was likely performed with curative intent in a substantial proportion of patients. Chemotherapy was administered in 26.6% of XRT patients. Ten-year overall and disease specific survival for patients receiving primary radiation was 18.3% and 48.8%, respectively, which compared to 37.3% and 64.3% in patients undergoing cystectomy (p < 0.01).
Patients who received primary RT tended to be older and had a reduced overall and disease specific survival. While the survival differences may reflect bias in patient selection, there is also some evidence that RT is not being delivered in an optimal fashion. Specifically, only a small percentage of patients received concomitant radiosensitizing chemotherapy We are expanding the dataset to assess the presence of adverse risk factors (eg. associated hydronephrosis or carcinoma in situ) in patients undergoing RT, to assess the adequacy of pre-RT TURBT and also to assess post-RT urologic surveillance. This data will be used to initiate a prospective quality assurance initiative with the ultimate goal of establishing a multidisciplinary clinic for all patients with invasive bladder cancer.
Increasing data advocates the wider use of partial nephrectomy for renal tumours amenable to this approach. We report the first North American use of this new parenchymal clamp for use in both laparoscopic and open partial nephrectomies.
Constructed with approximately 1 cm wide flat nitinol band; the device can be placed through a 10 mm laparoscopic port. The device is sterilizable, and can be reused a limited number of times. Operative technique followed standard technique: differences included that the renal hilum was not dissected out and the perirenal fat and renal capsule were dissected further than usual in order to facilitate placement of the clamp away from the edge of the tumour resection.
|Patient||Operative approach||Pre-op size of tumour (cm)||Side||Collecting system entry||Operative time (min)||Clamp time (min)||EBL (cc)|
|Patient||Pathology||Margins||Maximal dimension (cm)|
|1||Papillary RCC, Furhman grade 3/4||Negative||1.8|
|2||Clear cell RCC, Furhman grade 1/4||Negative||3.2|
|3||Clear cell RCC, Furhman grade 2/4||Negative||4.0|
Three elderly patients (74 year old man(1), 70 year old lady(2) and 72 year old man(3) underwent partial nephrectomy; operative, pathology and laboratory results are summarized in Tables 1–3. Patients were discharged on postoperative day 3, 5 and 6 respectively. An intraoperative photograph of patient #3 is shown in Fig. 1.
In our small series, we found this parenchymal clamping device to be a safe and useful adjunct to partial nephrectomy.
|Patient||Pre-op Hgb||POD #1 Hgb||Post-op Hgb nadir||Pre-op Cr||Cr POD #1||Post-op Cr Nadir|
To evaluate the effect of cold ischemia during open partial nephrectomy on postoperative renal function and compare it to warm ischemia during laparoscopic partial nephrectomy.
We reviewed our oncologic database for partial nephrectomy at The Ottawa Hospital from 2002 to 2008. There were 145 consecutive patients who underwent partial nephrectomy for renal masses. Patients with single kidney (n = 17) and those with unknown hilar clamp time (n = 7) were excluded from the analysis. There were 120 patients included in the analysis. Eighty-three patients (69.2%) had an open approach while 37 patients (30.8%) had a laparoscopic approach. Cold ischemia was achieved with ice-slush renal surface cooling for 10 to 15 minutes in all but 1 patient undergoing open partial nephrectomy and this was also excluded from analysis. All patients undergoing laparoscopic partial nephrectomy underwent warm ischemia. Cockroft-Gault estimates of creatinine clearance (CrCl) were calculated preoperatively and at 3 months postoperatively. The primary outcome was change between preoperative and postoperative CrCl. Univariate and multivariate analyses controlling for age, sex, ischemia time, preoperative CrCl, co-morbid conditions namely diabetes mellitus, hypertension as well as estimated blood loss were performed to assess the effect on postoperative renal function as measure by change in CrCl.
Mean patients’ age was 59.3 years. The overall baseline CrCl was 86.8 ml/s (82.9 and 95.4 ml/s for the open and the laparoscopic approaches respectively). Overall mean tumour size was 2.7 cm (open = 2.8 cm and laparoscopic = 2.5 cm, p-valu e= 0.16). Overall mean ischemia time was 32.7 minutes. Mean ischemia time was 35.4 and 26.6 minutes for the open and laparoscopic approaches respectively (p < 0.0001). Mean change in CrCl was 7.4 ml/s for patients who had open partial nephrectomy and 3.2 ml/s for those who had laparoscopic partial nephrectomy. In both univariate and multivariate analyses, change in CrCl was significantly affected by ischemia time (p = 0.01 and 0.04 respectively), and baseline CrCl (p = 0.001 and 0.0004 respectively). The surgical approach (open vs. laparoscopic) was not a significant predictor in univariate or multivariate analysis (p-value = 0.06 and 0.14 respectively).
The surgical approach of partial nephrectomy, laparoscopic or open does not significantly affect change in postoperative renal function measured by CrCl. As all patients treated with open partial nephrectomy underwent cold ischemia whereas all laparoscopic treated patients had warm ischemia these results also suggest similar renal function preservation with both ischemic modalities. The strongest predictors affecting the change in postoperative renal function are ischemia time and preoperative renal function. Randomized trials comparing cold vs. warm ischemia are needed to evaluate their effect on postoperative renal function.
The costs of follow-up strategies in patients after radical nephrectomy for primary renal cell cancer (RCC) have not been evaluated. We compared the costs of two different surveillance strategies, the new Canadian Urological Association (CUA) Guidelines and the old strategy implemented in our institution.
With institutional ethics review, 75 patients who underwent radical nephrectomy for primary non-metastatic renal cancer were retrospectively reviewed. Patients were scheduled for follow-up at 3, 6, 12 months and then yearly until recurrence was detected or the 60 months mark was reached. During each visit patients underwent history, physical exam, laboratory testing (CBC, electrolytes, renal and liver panels), urinalysis, and chest x-ray. At the 6 month visit CT chest/abdomen/pelvis was performed for all patients. After 12 months a stage-based strategy of surveillance was implemented. For T1, no imaging was ordered unless symptoms were present. For T2/3, CT was considered at the 2 year mark or if symptoms were present. The estimated costs following the CUA guidelines and our old institutional protocol were compared.
The distribution of our patients stage by stage was T1 41, T2 15, and T3 19 patients. Our mean follow up was 31.1 (± 20.4 SD) months. The overall and disease-free survival were 87.7% and 85.2%. Total medical costs were higher for our old Institutional surveillance strategy than the CUA guidelines ($181 861 vs. $135 054). For the complete follow-up of 75 patients a cost savings of $46 806 could have been achieved following the CUA guidelines (p = 0.0019). Of recurrences 6 out of 7 were detected by routine screening, only one recurrence was identified by symptoms. The cost per recurrence detected in our old protocol was $9812.92. The increased cost of our institution analysis was due to more visits with basic testing, symptomatic investigation, and follow-up of imaging tests. The cost attributable to these extra tests was a median of 15% (range of 0–59%).
Based on our results we endorse the new CUA surveillance strategy for RCC follow-up. Significant cost savings would be achieved by changing from our older follow-up strategies used at our institution.
The incidence of small renal masses (SRM) has risen dramatically over recent years secondarily to the increased use of modern imaging techniques. The partial nephrectomy has become the standard of care for SRM’s in appropriately selected cases. Performing a laparoscopic partial nephrectomy is technically challenging with a lengthy learning curve and may have associated prolonged warm ischemic time. The use of robotic assistance may enhance surgical resection, reconstruction and decrease warm ischemic time in complex renal masses. We describe the first twelve patients treated by way of robotic assisted laparoscopic partial nephrectomy (RALPN) at a tertiary centre in Canada.
Patient records and databases were reviewed for the first twelve consecutive patients treated with RAPLN for SRM’s. Patient demographics, tumour characteristics, intra-operative and postoperative data has been collected retrospectively.
Mean patient age was forty-nine (s = 14.2). Median ASA and mean BMI were 2.1 (s = 0.67) and 30.4 kg/m2(s = 0.58) respectively. Preoperatively four patients suffered from renal insufficiency and one patient had a solitary kidney. Mean tumour size was 2.73 cm (s = 1.28) in maximum diameter. 8/12 of tumours treated were right sided and 6/12 of masses were endophytic. Pathology revealed seven RCC clear cell carcinomas, three RCC papillary carcinomas, one oncocytoma and one angiomyolipoma. Mean operative time and warm ischemic time were 229 minutes (s = 96.6) and 24 minutes (s = 5.4) correspondingly. Intra-operative ultrasound was used in all twelve cases. Hilar control was obtained with use of a Satinsky clamp in 9/12 cases and laparoscopic bulldog clamps in 3/12 cases. One case was converted to open due to failed hilar control. Mean estimated blood loss was 365 ml (s=61.7). All cases had negative resection margins. Mean length of hospital stay was 3.3 days (s = 0.72). No postoperative complications occurred. Mean delta creatinine at 3 months postoperatively was 5% (± 8%) There has been no evidence of recurrence in all 12 cases. Follow up ranges from 5 to 21 months.
The robotic partial nephrectomy is a viable and successful alternative to open and laparoscopic nephrectomy in selected cases. The enhanced ergonomics, wrist emulating mobility and visualization allow for improved partial nephrectomy techniques. The robotic advantages must be weighed against its increased cost in order to determine its practicality versus more customary methods of treatment. Further studies and longer follow-up are required to substantiate the use of this new technology.
The prognostic significance of advanced age on cancer-specific mortality (CSM) after nephroureterectomy (NU) for invasive upper urinary tract urothelial cancer (UTUC) is controversial. We assessed the effect of advanced age on CSM after NU in a large population-based cohort.
We relied on 2824 patients, who were treated with NU for UTUC in 9 Surveillance, Epidemiology, and End Results registries, between 1988 and 2004. Using the most significant cut-off values, age was stratified into three strata: ≤59 years vs. 60 to 79 years vs. ≥80 years. Differences in the rates of CSM were assessed using cumulative incidence plots that account for other-cause mortality. Univariable and multivariable competing-risks regression models were used to assess the effect of age on CSM.
The 5-year cumulative CSM rates were respectively 14.8, 19.6, and 23.6% for patients ≤59 years of age, 60 to 79 years of age, and ≥80 years of age (Gray, p < 0.01). After accounting for other-cause mortality, the 5-year OCM rates for the same age groups were respectively 14.7, 28,4, and 47.5% (Gray, p ≤ 0.001). Advanced age reached independent predictor status of CSM in competing-risks regression analyses (p ≤ 0.045).
Advanced age was found to be an independent predictor of CSM after NU, even after controlling for the potentially confounding effect of other-cause mortality. In consequence, the deleterious effect of advanced age that may be related to postponed surgery should be considered in clinical decision-making.
The impetus to perform partial nephrectomy (PN), or nephron-sparing surgery, for renal cell carcinoma (RCC) has increased in the past decade from strictly patients with imperative indications for the surgery, such as the presence of a solitary kidney or bilateral tumours, to include those with a normal contralateral kidney (elective indication). This has been largely due to the early detection of incidental small renal lesions and better surgical techniques that achieve satisfactory cancer outcomes and minimize peri-operative morbidity, with results similar to radical nephrectomy (RN). We further explored the potential benefits of this surgery by conducting a systematic review on the impact of PN on postoperative renal function in comparison to RN.
We searched MEDLINE for all relevant articles published up to July 31, 2008. We included all randomized-controlled trials (RCTs), cohort studies, and case-based studies that were published in English or French and compared outcomes for PN or RN, specifically postoperative renal function. Two independent reviewers abstracted relevant data and performed quality assessments on each selected study. We compared pre- and postoperative renal function, as a measure of changes in serum creatinine, estimated glomerular filtration rate (eGFR), creatinine clearance (CrCl), or need for dialysis for both PN and RN groups.
We identified 210 unique citations, of which 16 cohort studies (1 prospective, 15 retrospective) met our inclusion criteria. Studies were grouped and compared according to the indication for performing PN—imperative (1 study), elective (8 studies), or a mixture of both (7 studies). All 8 elective studies showed no difference in postoperative renal function in patients undergoing PN, and a significant worsening of renal function in the RN group. Furthermore, postoperative complications and cancer-related morbidity and survival outcomes were similar in both groups, although study durations were relatively short.
PN appears to better-preserve postoperative renal function compared to RN for small renal tumours, while maintaining similar surgical and cancer-specific outcomes. Whenever feasible, a nephron-sparing approach should be utilized to minimize any future progression to chronic renal insufficiency.
Extirpative surgery is the gold standard treatment for renal cell carcinoma. Surgical options for patients include radical and partial nephrectomy, by both open and laparoscopic approaches. Recent data has shown that postoperative renal function is an important predictor of overall survival following both radical and partial nephrectomy, particularly for early stage tumours. The aim of our study was to analyze our centre’s experience with radical and partial nephrectomy with respect to postoperative renal function outcomes.
The Alberta Urology Institute Nephrectomy Database is a comprehensive single institution database which aims to collect demographic, oncologic, renal function, surgical, and survival outcomes for patients who receive surgical therapy for renal cell carcinoma. A total of 281 patients charts from 2001 to 2009 have been abstracted thus far and entered into the database.
There were 281 patients analyzed, comprising 126 radical and 151 partial nephrectomies. There were147 patients who had T1a lesions, 82 T1b, 45 T2, and the remaining 8 T3-T4. In the T1a group, there was no significant difference in mean GFR change between radical and partial nephrectomy groups. Twenty-two patients (15%) received radical nephrectomy, and 125 (85%) received partial nephrectomy. In the radical nephrectomy group, 11 patients (50%) with previously normal GFR developed a GFR between 30–60 mL/min, compared to 31(25%) in the partial nephrectomy group (p < 0.01). The odds ratio for developing renal dysfunction following radical nephrectomy in this group was 4.7 (95% CI = 1.8–11.9). In the T1b group, 52 patients received radical nephrectomy, compared to 29 who received partial nephrectomy. There was no significant difference between development of renal insufficiency in these two groups, which likely attributes to a higher proportion of patients in the partial nephrectomy group having baseline renal impairment compared to those receiving radical nephrectomy (20% vs. 5%). Fifteen patients (33%) in the T2 group developed new renal insufficiency. Five mortalities were noted in this cohort at mean 2.6 years follow up, 3 of which were specific to renal cell carcinoma.
In the therapy of early stage renal cell carcinoma, particularly for T1a lesions, radical nephrectomy is a significant predictor of renal insufficiency. Our data is consistent with others, but will require further maturation for analysis of overall and cancer specific survival. Hopefully a National Data will be able to determine the cut-point for recommending partial vs. radical nephrectomy. These early results stress the importance of partial nephrectomy in the treatment of these lesions for preservation of renal function.
The incidence of renal cell carcinoma (RCC) in renal transplant recipients has been estimated at 30 or more times that seen in the general population. This study was undertaken to assess the prevalence of RCC in a large single-center recipient population, and to determine the histologic class and outcomes of these tumours and patients.
We examined the outcomes of patients undergoing renal transplantation at our institution between 1975 and 2008 to determine the incidence of renal masses occurring in the native and allograft kidneys of the recipients. Tumour histology was determined, and the follow up and outcomes of the patients were assessed. Surveillance imaging was performed with ultrasound evaluation of the allograft and native kidneys.
There were 2626 patients who received a cadaveric (n = 1866) or living-related (n = 769) renal allograft. Thirty-two renal masses were diagnosed in the native kidneys of 27 patients (1.0%; male = 21, female = 11), and 6 tumours were found in renal allografts (0.2%; male = 5, female = 1). All tumours were discovered incidentally. Mean age at diagnosis was 50.8 years for native kidney tumours and 49.2 years for allo-graft tumours. Mean duration of dialysis prior to transplantation was 4.2 years, and mean interval between transplantation and RCC diagnosis was 9.6 years in native kidneys (range 0.6–29.3 years) and 10.0 years for transplant kidneys (range 0.8–22.1 years). Mean diameter of the masses in native kidneys was 3.07cm (range 0.5–8.0cm). Clear cell carcinoma was the most common histology (n = 17) followed by papillary RCC, which was diagnosed in 13 cases (11 type 1, and 2 type 2). There was one chromophobe RCC and one tubulocystic carcinoma. In allograft kidneys, 3 clear cell RCC and 3 papillary RCC were diagnosed. Univariate analysis did not find any variable to be predictive in determining pathology. Native kidney tumours were managed with radical nephrectomy by an open (n = 18) or laparoscopic (n = 14) approach, while allograft tumours were managed by nephrectomy (n = 2), partial nephrectomy (n = 2) or radiofrequency ablation (n = 2). At a mean follow-up of 5.1 years following native nephrectomy, 21 patients are alive, one of whom has metastatic RCC. Three patients have died from non-cancer causes and 3 patients have been lost to follow up. Five patients with allograft tumours are alive at a mean of 5.5 years post-treatment, and one is lost to follow-up.
Renal cell carcinoma is more common in patients with end-stage renal dysfunction and renal transplantation. Routine screening imaging can identify suspicious masses, which most commonly represent RCC, though the pattern of subtype differs from the general population. Survival rates are good at 5 years following diagnosis and management.
Surgical resection is the optimal curative treatment for localized renal cell carcinoma (RCC). Although RCC invades the venous system in 4–9% of newly diagnosed patients, there is little published data on the prognostic significance of a positive renal vein resection margin following radical nephrectomy. We present an analysis of RCC patients with renal vein invasion at Vancouver General Hospital (VGH) within the last 10 years and the impact of renal vein resection margin status on disease specific survival.
Patients who were treated with radical nephrectomy for renal vein invasive RCC were identified in the VGH pathology database. Data on clinical outcomes, demographics, pathological features and clinical staging of these patients was analyzed and used to compare outcomes between those with positive and negative resection margins.
Of 157 patients treated with radical nephrectomy for RCC between 1998 and 2008, 20 (13%) had invasion of the renal vein; 5 of these had a positive renal vein resection margin. Disease specific survival at 5 years was significantly worse in patients with positive renal vein resection margins (p = 0.03). Of the 5 patients with positive margins, 2 had distant metastases at diagnosis and 2 developed distant metastases during follow-up. All positive margins patients died of their disease within 5 years of nephrectomy. Of the 15 patients with a negative renal vein resection margin, 1 had distant metastases at diagnosis and 2 developed metastasis during follow-up. These patients died of their disease within 5 years of nephrectomy, one further patient died of local recurrent greater than 5 years after nephrectomy. Eight patients with negative margins were disease free after an average follow-up of 59.5 months.
For RCC patients with pT3b/c disease, a positive renal vein resection margin is a dire prognostic indicator. The experience at this institution reveals that these patients have very poor outcomes whether or not there is local tumour invasion or nodal involvement. Complete resection achieving negative renal vein margins is essential to provide the best chance of long-term, disease-free survival.
While the relative merits of laparoscopic and image-guided percutaneous approaches to renal radiofrequency ablation (RFA) have been defined and debated, there is scant data directly comparing their relative clinical efficacy, durability, and safety. The purpose of this study is to compare the outcomes of our single-centre experience with laparoscopic and percutaneous renal RFA.
A retrospective chart review encompassing 34 tumours in 30 patients was conducted. Twenty-one tumours (62%) were ablated laparoscopically, while 13 tumours (38%) were ablated percutaneously using CT guidance. Renal biopsies were performed in all but 4 tumours, and all ablations were performed using RITA probes. Cross-sectional imaging (CT or MRI) was performed six weeks post-ablation and at 6 to 12-month intervals thereafter. Statistical comparisons were performed using Student’s t-test and Fisher’s exact test.
The laparoscopic and percutaneous groups were similar in their preoperative and tumour characteristics. Mean patient age in the laparoscopic and percutaneous groups were 64.3 and 64.1 years, respectively, and mean tumour size was 2.3 cm and 2.7 cm, respectively. Laparoscopic ablations did include more ablation cycles than percutaneous ablations (2.9 vs. 2.1, p = 0.007). All three incomplete ablations occurred in patients treated percutaneously, yielding a primary efficacy rate of 77% in the percutaneous group and 100% in the laparoscopic group (p = 0.05). At a median follow-up time of 27 months, there was one recurrence in the laparoscopic group (5%) and none in the percutaneous group (p = NS). Length of hospital stay and change in GFR were not significantly different between the groups. Two major complications, a urine leak and ureteropelvic junction obstruction, were encountered, with both complications occurring in patients treated laparoscopically (p = NS).
In our series comparing laparoscopic and percutaneous RFA, the percutaneous approach yielded a higher rate of incomplete ablation, a finding that likely reflects less aggressive probe repositioning and fewer ablation cycles. The clinical significance of this finding on long-term oncologic outcomes is yet to be determined. Conversely, laparoscopic RFA was associated with the two major complications encountered in this series. These issues of relative safety and efficacy must be carefully balanced when choosing a RFA approach.
Open nephrectomy (OPN) and laparoscopic radical nephrectomy (LRN) may be underutilized. We explored the rates of the two surgeries relative to open radical nephrectomy (ORN) in a large population-based database.
Between 1998 and 2008, a total of 17690 nephrectomies for non-metastatic renal cell carcinoma were performed in the state of Florida. Of these, 2528 (14.3%, 1379 (7.8%) and 13783 (77.9%) respectively represented OPN, LRN, and ORN. We examined the proportion of patients who underwent an OPN, LRN, and ORN throughout the study period. Multivariable logistic regression analyses addressed predictors of either OPN or LRN after adjusting for patient age, gender, race, Charlson comorbidity index, insurance type, and year of surgery.
Overall, the rate of OPN increased from 8.1 to 18.7% over the study period vs. from 0.2 to 12.3% for LRN (chi-square trend: p < 0.001). OPN and LRN rates ranged respectively from 9.6 to 25.1% and from 0.3 to 12.2% in individuals <60 years old from 6.4 to 12.7% and from 0.4 to 13.5% in individuals >70 years old. Similarly, OPN and LRN rates ranged from 13.0 to 24.2% and from 0.3 to 11.7% in the highest annual hospital volume tertile vs. 4.7 to 14.7% and from 0.2 to 10.4% in the lowest annual hospital analyses, high hospital volume and high surgical volume were independent predictors of the use of OPN and the use of LRN (p < 0.001).
OPN and LRN are performed significantly less frequently than ORN. Both hospital and surgical volume represented important determinants of OPN and LRN use. This implies that the likelihood of being treated with either OPN or LRN is the highest when the surgery is performed at high volume centres and by high volume surgeons.
Cytoreductive nephrectomy (CNT) may improve survival of patients with metastatic renal cell carcinoma (mRCC). However, it may be associated with higher morbidity and mortality rates relative to nephrectomy in non-mRCC patients. We assessed the peri-operative outcomes of CNT in patients with mRCC and compare these to outcomes of individuals who underwent a nephrectomy for non-mRCC in a large population-based dataset.
Between 1988 and 2008, 1985 and 27037 patients underwent a nephrectomy for respectively mRCC and non-mRCC using the Florida database. We examined patient characteristics, complications and perioperative mortality rates of patients with mRCC who underwent a CNT and we compared those with the characteristics and outcomes of individuals with non-mRCC.
Relative to non-mRCC individuals, a larger proportion of mRCC patients were males (67.9 vs. 61.6%; p < 0.001) and represented emergency admissions (27.5 vs. 19.4%; p < 0.001). Length of stay was statistically significantly longer in patients with mRCC relative to their non-mRCC counterparts (9.5 vs. 6.7 days; p < 0.001. The overall complication rate was also higher in mRCC patients (29.6 vs. 22.8%; p < 0.001). Specifically, the rates of accidental intraoperative lacerations (5.6 vs. 3.6%; p < 0.001), postoperative cardiac complications (4. Vs. 2.4%; p < 0.001), vascular complications (2.5 vs. 0.8%; p < 0.001), respiratory complications (8.4 vs. 6.4%; p = 0.001), hemorrhage (2.6 vs. 1.4%; p = 0.02) were higher in patients with mRCC. Perioperative in-hospital mortality rate was also higher in mRCC patients (3.0 vs. 1.2%; p < 0.001). In multivariable logistic regression models, after adjusting for patient age, gender, race, insurance type, average annual surgical and hospital volume, mRCC was a statistically significant predictor of any complication type (OR: 2.7 [95% CI: 2.0–35]; p < 0.001), and predicted higher perioperative mortality (OR: 1.4 [95%CI: 1.3–1.6]; p < 0.001).
Nephrectomy in individuals with mRCC is associated with higher complication and perioperative mortality rates relative to nephrectomy performed in patients with non-mRCC. This information should be included in informed consent. Moreover, careful patient selection is critical to minimize morbidity and mortality after CNT.
Small renal masses between 1.1 and 4.0 cm can be visualized and confirmed histologically with a high degree of certainty. We examined the rate of synchronous metastases (SM) in patients with renal cell carcinoma (RCC) 1.1 to 4.0 cm in size within a large population-based tumour registry.
We tested the relationship between tumour size and SM in a population of 27 780 patients with small renal masses diagnosed and/or treated with nephrectomy for histologically-proven RCC within 17 SEER registries between 1988 and 2006. Cubic spline analyses and logistic regression models were used to test this relationship after adjusting for other covariables, such as age, gender, race, RCC histological subtype and year of diagnosis.
Within the study population the rate of SM was 4.5%. Stratification according to 1 cm tumour size intervals revealed that the SM rate increased with increasing tumour size: 1.1–2.0 cm: 3.1%; 2.1–3.0 cm: 4.0%; 3.1–4.0 cm: 5.7% (χ2 trend; p < 0.001). Cubic spline analysis showed that rate of SM is starts to increase exponentially when tumour size exceeds 2.5 centimeters. Continuously coded tumour size represented an independent predictor of SM in multivariate regression models (OR: 1.04; p < 0.001). When tumour size was divided into 1 cm intervals, patients with 2.1–3.0 and with 3.1–4.0 cm RCCs had respectively a 1.2- and a 1.7-fold higher risk of harboring SM (p ≤ 0.05). Finally, advanced age (p < 0.001), male gender (p < 0.001), African-American race (p = 0.03) and more contemporary year of diagnosis (p = 0.02) also represented independent predictors of SM.
Tumour size is related to SM rate even in patients with small (1.1 to 4.0) RCCs. The rate of SM increases exponentially when tumour size exceeds 2.5 cm. Conversely, no differences in metastatic rates were observed below this threshold.
Although surgical resection is still the gold standard therapy for localized renal tumours, patients with multiple bilateral tumours and/or significant comorbidities present a clinical challenge. Percutaneous radio frequency ablation (RFA) provides an alternative to minimize morbidity in selected patient cohort. The goal of the current study was to evaluate the role of RFA in the management of renal tumours in an academic centre.
A retrospective chart review of all renal tumour patients treated with RFA was performed. Patients were followed with CT and/or MRI according to their renal function. Procedure success was assessed by the absence of tumour enhancement and progression on imaging.
From 2005, a total of 27 patients (19 males and 8 females) with 32 renal tumours underwent CT guided RFA under general anesthesia by a single operator. Median tumour size was 2.8 cm (mean 3.1, range: 1.4 – 5.4 cm). Five patients required a 2nd RFA procedure. Patients received from 1 to 5 ablations per tumour. Median age was 72 years (range 39–95). All patients had either solitary kidney, bilateral disease or considered unfit for surgery due to significant comorbidities. Mean patient follow-up was 2.7 years. Post-RFA complications were; minor bleeding and hematoma (n = 5), no response and nephrectomy (n = 1), residual tumours (n = 2), recurrent tumour (n = 1), worsening renal functions (n = 2) of which one required permanent dialysis, pneumothorax (n = 2), splenic injury (n=1), hepatic puncture (n = 1), duodenal fistula (n = 1), urinoma (n = 2), perirenal abscess and emphysematous pyelonephritis (n = 1), renal cortical infarction (n = 1), deep cutaneous burn (n = 1), wrist drop (n = 1) and psoas injury (n = 1).
Even though RFA can be a reasonable successful alternative management modality for a selected patient cohort with renal tumours, it can still carry a significant risk for serious complications.
There is increasing evidence that partial nephrectomy improves outcome in terms of renal function and overall survival. Our study objective was to determine if practice patterns in a contemporary population had evolved to reflect this finding.
Between 2001 and 2009, 363 patients underwent surgical excision of a renal mass at a single tertiary-care centre. A retrospective analysis was conducted to assess patient demographics, tumour characteristics and surgical management during this period. Odds ratios and 95% confidence intervals were calculated per year increase for clinical stage ≥2, female gender, malignancy, tumour size >4, lap surgery, partial surgery, as well as partial surgery within open and lap access separately.
The average patient age decreased from 65.2 ± 13.8 in 2001–03 to 59.8 ± 12.5 in 2008–09 (−0.77 SE(0.37), p = 0.035) with a significant increase in the proportion of female patients (odds ratio 1.82 (1.54, 2.15), p < 0.05). The incidence of benign tumours increased from 7.8% in 2001–03 to 23.2% in 2008–09 for an odds ratio of 0.79 (0.67, 0.94, p < 0.05), while clinical stage remained unchanged (odds ratio 1.02, 95% CI (0.89, 1.17). The incidence of partial nephrectomy as the surgery of choice increased from 33.3% in 2001–03 to 49.3% in 2008–09 (odds ratio 1.19 (1.05, 1.35, p < 0.05) despite the average tumour size remaining unchanged (0.067 SE(0.11), p = 0.56, 4.94 ± 3.3 in 2001–03 and 5.33 ± 4.3 in 2008–09). Between 2001–03 and 2008–09, partials increased from 33.3% to 57.6% amongst patients undergoing open surgery and from 0% to 41.7% amongst patients undergoing laparoscopic surgery. Surgical access evolved from 100% open approach in 2001–3 to 52.2% performed laparoscopically in 2008–09 (odds ratio 1.82 (1.54, 2.15), p < 0.05).
We noted a significant decrease in patient age during the study period, which may be secondary to earlier detection in addition to increased utilization of active surveillance and ablative therapies in older patients. There was a significantly increased employment of partial nephrectomy, via open and laparoscopic approach, despite tumour size remaining unchanged. This lack of size difference was unexpected but potentially due to the nature of referrals to a tertiary-care centre. The increased likelihood of benign disease reinforces the need for nephron-sparing approaches.
To compare outcomes of patients ≥70 years of age undergoing laparoscopic partial nephrectomy (LPN), laparoscopic radical nephrectomy (LRN) and laparoscopic ablative therapy (LAT) for small renal masses.
From a prospectively maintained database we identified 19 (LRN), 28 (LPN), and 19 (LAT) patients aged ≥70 who underwent surgery for cT1aN0M0 lesions. Perioperative, surgical and functional outcomes were compared.
The 3 groups were similar in age, race, BMI, and estimated creatinine clearance (eCrCl). In the LRN group, mean tumour diameter was larger (3.3 cm vs. 2.4 cm (LPN) and 2.7 cm (LAT); p = 0.0005) and there was a higher percentage of central tumours (73.7% vs. 25.0% and 5.3 %; p < 0.0005) when compared to the LPN and LAT groups, respectively. Although intra-operative and postoperative complication rates were similar, mean estimated blood loss and operative time were highest in the LPN group (p < 0.05). Moreover, 42.1%, 39.3% and 42.1% of patients had preoperative stage 3 chronic kidney disease (CKD) in the LRN, LPN and LAT groups, respectively. Patients who underwent LRN had a lower follow-up eCrCl (43.4 mL/min vs. 61.4 (LPN) and 59.2 (LAT); p < 0.01) and a higher likelihood of developing stage 3 CKD after treatment (100% vs. 25.0 (LPN) vs. 18.2 (LAT); p < 0.0005).
Impaired renal function is common in elderly patients presenting with renal masses. LPN and LAT provide superior preservation of renal function when compared to LRN in this population. In appropriately selected patients ≥70 years of age presenting with T1a renal lesions, laparoscopic nephron-sparing approaches should be considered.
There is much debate as to the prognostic significance of lymph node yield and positive number of lymph nodes within a retroperitoneal lymph node dissection (RPLND) specimen. We examined the effect of number of lymph node removed and examined and number of positive lymph nodes on cancer specific mortality within a population-based cohort of patients with nonseminomatous germ cell testicular tumours (NSGCTT).
Between 1988 and 2006, 1919 RPLNDs were performed within 17 Surveillance, Epidemiology and End Results (SEER) registries. Of these, 1024 (53.4%) were performed for stage I and 895 (46.6%) were performed for stage II NSGCTT. Univariable and multivariable Cox regression models tested the prognostic impact of either number of removed/examined lymph nodes or number of positive lymph nodes on cancer specific mortality. Analyses were adjusted for age, race (white, black, other), year of surgery (1988–1992, 1993–1997, 1998–2002, 2003–2006), socio-economic status (low vs. high) SEER stage (I vs. II) and SEER registry.
The mean number of lymph nodes removed/examined was 21.9 (range: 1–96). The mean positive nodes were 1.6 (range:0–56) across all stages. The mean number of lymph nodes removed/examined and of positive lymph nodes were 21.3 and 22.6 vs. 0 and 3.4 for respective stages I and II NSGCTT. In univariable and multivariable Cox regression analyses neither number of lymph nodes removed/examined (p = 0.6, p = 0.8) nor number of positive lymph nodes (p = 0.7, p = 0.2) were able to reach independent predictor status for cancer-specific mortality. Among covariates the only variable that was an independent predictor of cancer specific survival was advanced age (p = 0.001).
Cancer-specific mortality does not seem to be influenced by the number of nodes in the surgical specimen or the number of positive lymph nodes across stages I and II NSGCTT.