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Bombesin and gastrin-releasing peptide (GRP) are potent neuropeptides expressed by prostate cancer neuroendocrine cells and are related to the progression of this malignancy. This study characterizes bombesin receptors in human prostate cancer cell lines (PC-3, DU-145, LNCaP) and assesses the in vitro effect of bombesin on signal transduction and cell proliferation. [125I]Tyr4-bombesin binding assays (37 °C) and Scatchard analyses revealed the presence of a single class of high-affinity receptors with similar Kd values (1·5, 1·1 and 3·6 × 10−10 m in PC-3, DU-145 and LNCaP cells respectively) but with significant differences in the number of binding sites per cell (47·6, 1·5 and 0·1 × 103 in PC-3, DU-145 and LNCaP cells respectively). Molecular characterization of the binding sites performed in PC-3 cells by cross-linking experiments and SDS/PAGE revealed a single radioactive band of 85 kDa. To determine which of the three known bombesin receptor subtypes (GRP receptor (GRP-R), neuromedin B receptor, bombesin receptor subtype-3) were expressed in the cell lines, reverse transcription/PCR analysis of cellular RNA followed by hybridization with receptor-specific cDNA was performed. This revealed the presence of GRP-R transcript in all cell lines, while neither of the other two receptor transcripts were expressed. When intracellular calcium mobilization was measured by Fura-2/AM cell labeling and spectrofluorometric monitoring, bombesin (100 nm) induced rapid calcium mobilization in both PC-3 (>200% of baseline) and DU-145 (>100% of baseline) cells, but not in LNCaP cells. However, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and [3H]thymidine incorporation, no growth modulation was observed with bombesin or bombesin receptor antagonist at various concentrations (0-500 nm). Our data indicate that bombesin is a potent inducer of signal transduction via GRP-R receptors in androgen-insensitive PC-3 and DU-145 prostate cancer cells. This suggests that the bombesin/GRP family of neuropeptides may play a regulatory role in the biology of androgen-independent prostate cancer.

PURPOSE We report our experience with simultaneous resection of residual masses above and below the diaphragm in patients with metastatic nomseminomatous germ cell tumor (NSGCT) of the testis. MATERIALS AND METHODS Twenty-four patients underwent simultaneous resection of residual postchemotherapy masses in the retroperitoneum and chest, including three who also had radical neck dissection. All had been heavily pretreated with chemotherapy and five had undergone previous retroperitoneal lymph node dissections (RPLNDs). RESULTS The combined procedure was performed with no mortality and low morbidity. The median length of the procedure was 5 hours 45 minutes, median blood loss 500 mL, and median length of hospital stay 9 days. Complications included one patient with chylous ascites and one with a prolonged air leak, both of which resolved with conservative management. Eighteen patients had similar pathologic findings in all sites: 13 with necrosis only and five with teratoma only. Six patients had discordant pathology in the abdomen and chest, including one with viable tumor in the chest only and two with viable tumor in the abdomen only. The overall actuarial 5-year survival rate for all patients was 79%. CONCLUSION Simultaneous resection of neck, chest, and abdominal residual masses after chemotherapy for germ cell tumors is both a feasible and safe alternative to staged excision in selected patients who require surgical intervention at multiple sites and fulfills the objective of rendering patients disease-free in a single operative procedure.

The main objectives of this study were to reassess complications associated with transrectal ultrasound-guided biopsies (TRUSBx) of the peripheral zone (PZ) and to compare morbidity of exclusive PZ biopsy to morbidity associated with two additional transition zone (TZ) biopsies. We distributed a self-administered questionnaire assessing TRUSBx complications to 883 consecutive patients who underwent two systematic TZ TRUSBx in addition to systematic sextant PZ TRUSBx, and to 383 consecutive patients who underwent exclusive PZ TRUSBx. Of 316 (35.8%) patients subjects to TZ and PZ TRUSBx, 71% experienced hematuria, 63% hematospermia, 39% rectal bleeding, and 2.2% temperature elevation greater than 38°C. Of 137 (35.8%) patients who exclusively underwent PZ TRUSBx, 57%, 62%, 36%, and 1.4% reported these complications, respectively. Symptom duration and severity were similar in both groups. Although we report a substantially higher incidence of biopsy complications than previously published, these complications are self limited and require no intervention. Furthermore there appears to be no significant difference between complication rates associated with exclusive PZ biopsy compared with those associated with two additional biopsies of the TZ.

Introduction: Transperitoneal minimally invasive radical prostatectomy (MIRP) has become first choice for several urologists andpatients dealing with localized prostate cancer. We evaluate the effect of postoperative radiation on the small bowel in patients who underwent extraperitoneal open versus transperitoneal MIRP.Methods: We reviewed all patients who received postoperative radiation from 2006 to 2010. Planning target volume (PTV) and surrounding organs, including the small bowel, were delineated. The presence of the small bowel in PTV and its volume in receiving each dose level were analyzed.Results: A total of 122 patients were included: 26 underwent MIRP and 96 underwent open prostatectomy. The median age of patients was 66 years, with median body mass index 27 kg/m2. The total PTV dose was 66 Gy, with the minimum and maximum doses received by the small bowel 0.4 and 66.4 Gy, respectively. The maximum volume of small bowel that received the safe limit of 40 Gy was 569 cm3. Of the 26 patients who underwent MIRP, 12 (46%) had small bowel identified inside the PTV compared to 57 (59%) among patients who underwent open prostatectomy (p = 0.228). The mean volume of the small bowel receiving 40 Gy was 26 and 67 cm3 in open and MIRP groups, respectively (p = 0.006); the incidence of acute complications was the same in both groups.Conclusions: Higher volumes of the small bowel are subjected to significant radiation after MIRP procedures compared to open procedures; however, we could not demonstrate any impact on acute complications. Whether there is a difference in late complications remains to be evaluated.

Introduction: Our objective was to capture an overview of anticipated staffing needs at Canadian urology academic centres over the next 5 years to help guide and counsel urology residents in their respective programs.Methods: A 30-question survey was sent by email to all chairmen of academic urology divisions/departments during fall 2012. The first part of the survey solicited basic demographic information regarding number of residents, number of fellows and fellowships, and number of attending staff and affiliated hospitals. The second part of the survey included detailed questions on the number and sub-specialty of urologists needed at each respective institution, as well as the appropriate year of recruitment.Results: The response rate was 100%. There are 13 urology training programs across Canada located in 6 out of the 10 provinces. Robotic surgery is available at 9 out of the 13 centres. A total of 68 urologists need to be recruited by academic institutions throughout Canada within the next 5 years. The greatest need is for general urologists, with a total of 13 required. This is followed by 12 urologic oncologists needed, 11 female urology, 7 reconstructive urologists, 6 pediatric urologists, 6 endourologists, 5 transplant surgeons, 4 infertility/andrology, and 4 experts in advanced laparoscopy/robotics. There was no need for any urologic trauma surgeons in any academic institution surveyed.Conclusions: A total of 68 urologists need to be recruited into academic urology across Canada within the next 5 years. This crucial information can be used to help guide urology residents in choosing the most appropriate fellowship, in addition to providing them with an overview of future job prospects at academic institutions throughout the country.

To validate the prognostic relevance of lymph node density (LND) and identify its optimal cut-points in a large international multicenter series of patients treated with radical cystectomy (RC) for invasive bladder cancer.From 1993 to 2005, 4,430 bladder cancer patients who underwent RC without neoadjuvant chemotherapy were reviewed; of these, 1,038 were pN+M0 disease and form the basis of this report.Median age of patients was 67 years with median follow-up in survivors of 33 months. Overall, 5-year DSS estimate was 36%. Median number of lymph nodes removed was 18 (IQR, 11-32), median number of positive lymph nodes was 2 (IQR, 1-5), and median LND was 14.3% (IQR, 6.67-33.3%). LND as continuous variable was a stronger prognostic factor for DSS in patients that underwent a more extensive PLND (P0.001). HR for inverse association of LND with DSS increased incrementally with increasing LND cut-points. Categorizing LND into quintiles revealed strong tertiary distribution of risk based on LND6%, 6%-41%, or41% with cumulative 5-year DSS of 47%, 36%, and 21%, respectively (P0.001). When patients were stratified by adjuvant chemotherapy, LND remains independently prognostic in patients who received adjuvant chemotherapy as well as those who did not.Lymph node density is prognostic in bladder cancer patients who undergo a more extensive PLND and remains prognostic even when adjuvant chemotherapy is used. Prognostic value of LND is best represented as a continuum of risk and LND6% represents the best possible outcome in patients with nodal disease.

Systemic oxidative stress is associated with a wide range of pathological conditions. Oxidative DNA damage is frequently measured in circulating lymphocytes. Mitochondrial DNA (mtDNA) is known to be more sensitive to oxidative damage than nuclear DNA but is rarely used for direct measurement of DNA damage in clinical studies. Based on the supercoiling-sensitive real-time PCR method, we propose a new approach for the noninvasive monitoring of systemic oxidative stress by quantifying the mtDNA structural damage and copy number change in isolated lymphocytes in a single test. We show that lymphocytes have significantly less mtDNA content and relatively lower baseline levels of damage than cancer cell lines. In anex vivochallenge experiment, we demonstrate, for the first time, that exogenous H2O2induces a significant increase in mtDNA damage in lymphocytes from healthy individuals, but no repair activity is observed after 1 h recovery. We further demonstrate that whole blood may serve as a convenient alternative to the isolated lymphocytes in mtDNA analysis. Thus, the blood analysis with the multiple mtDNA end-points proposed in the current study may provide a simple and sensitive test to interrogate the nature and extent of systemic oxidative stress for a broad spectrum of clinical investigations.

Monoclonal antibodies CC49 and B72.3, which recognize a tumor associated glycoprotein (TAG-72) related to sialyted Tn antigen, have been used in clinical trials for radionuclide imaging, and treatment of colon, breast and ovarian carcinoma. In addition, studies with CC49 in patients with metastatic hormone refractory prostate cancer have been initiated based on the observed expression of TAG-72 in primary prostate cancer. We examined whether TAG-72 expression is a common feature of primary, metastatic and hormonally treated prostatic carcinoma.Immunohistochemical analysis of 25 primary prostatic carcinomas confirmed previous data that 21 of 25 specimens (80 percent) were immunoreactive with CC49. CC49 staining was noted in all 6 well (Gleason score 2 to 4), 8 of 10 moderately (Gleason score 5 to 6) and 7 of 9 poorly (Gleason score 7 to 9) differentiated tumors. CC49 immunoreactivity was noted in 10 of 20 hormonally treated prostate cancers and in 21 of 25 tumors without hormonal therapy. Intense C...

This initiative was undertaken in response to concerns regarding the variation in management and in outcomes of patients with bladder cancer throughout centres and geographical areas in Canada. Population-based data have also revealed that real-life survival is lower than expected based on data from clinical trials and/or academic centres. To address these perceived shortcomings and attempt to streamline and unify treatment approaches to bladder cancer in Canada, a multidisciplinary panel of expert clinicians was convened last fall for a two-day working group consensus meeting. The panelists included urologic oncologists, medical oncologists, radiation oncologists, patient representatives, a genitourinary pathologist, and an enterostomal therapy nurse. The following recommendations and summaries of supporting evidence represent the results of the presentations, debates, and discussions. Methodology

Purpose: We investigate the prostate specific antigen (PSA) response rate with nilutamide as a second line hormonal agent in patients with advanced prostate cancer in whom androgen ablation failed.Materials and Methods: From 1998 to 2001, 28 patients with hormone resistant prostate cancer were treated with nilutamide as second line hormonal therapy. Average patient age ± SD was 72.9 ± 9.1 years. Median time from diagnosis of cancer to hormone failure was 48 months (range 2 to 120). Median followup from initiation of nilutamide therapy was 26 months (range 15 to 44). All patients had previously received at least 1 antiandrogen (flutamide or bicalutamide) in addition to medical or surgical castration, which failed.Results: Upon initiation of nilutamide therapy 18 of the 28 patients (64%) had an initial reduction in PSA and 8 (29%) sustained a PSA response (greater than 50% decrease) beyond 3 months (range 3 to 21). PSA response to nilutamide in patients with a previous antiandrogen withdrawal respon...

INTRODUCTION : Radical cystectomy is the standard treatment for muscle invasive bladder cancer. We assessed clinical outcomes in patients found to have no evidence of disease (i.e., pT0N0) following radical cystectomy. METHODS : We collected and pooled a database of 2287 patients who underwent radical cystectomy between 1993 and 2008 in eight centres across Canada. Of this number, 135 patients were found to have pT0N0 bladder cancer at the time of cystectomy. Survival data and prognostic variables were analyzed using Kaplan-Meier method and Cox proportional hazard regression analysis. RESULTS : Median patient age was 66 years with a mean follow-up of 42 months. Clinical stage distribution was Tis 8.9%, Ta 1.5%, T1 20.7%, T2 45.2%, T3 5.2%, and T4 5.2%. The five-year recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were 83%, 96%, and 88%, respectively. The 10-year RFS, DSS and OS were 66%, 92%, and 70%, respectively. On Cox proportional regression analysis, no variables were associated with disease recurrence and only patient age was associated with overall survival. INTERPRETATION : Patients with pT0N0 pathology after cystectomy have excellent outcomes with high five- and 10-year RFS, DSS and OS. However, there is still a risk of tumour recurrence in this patient population and thus postoperative surveillance is still required.

What's known on the subject? and What does the study add? It is known that the majority (80%) of solid renal masses are malignant. Most of the literature suggests that smaller tumour size is associated with a higher incidence of benign disease. We have confirmed that decreased tumour size is associated with benign disease, particularly for lesions2 cm. Once radiologically apparent angiomyolipomas are excluded, the incidence of benign disease with small renal masses is lower than reported in the literature (11%). Furthermore, we have shown that small renal masses in females have a higher association with benign disease. Patient age and tumour location were not predictive of benign histology. We have also stratified our risks not only for benign disease but also for clinically indolent renal cancers to help physicians counsel patients with regard to managing these solid renal masses.• To determine the clinical predictors of benign disease in patients with solitary solid renal masses.• Pathology reports of patients who underwent radical or partial nephrectomy at two hospitals from 1998 to 2008 were reviewed. • Only patients with solitary solid unilateral renal masses were included. • Predictors of malignancy risk were assessed with univariate and multivariate logistic regression analysis.• A total of 592 patients with a mean (sd) age of 60 (13) years were included, 38% of whom were women. Radical and partial nephrectomy was performed in 66% and 34% of patients, respectively. • Renal masses were equally distributed on the right and left sides (49% vs 51%, P= 0.84). Masses were more commonly located in the upper and lower poles than in the mid pole (40.8% vs 38.7% vs 20.5%, respectively). • The mean tumour size was larger in patients who underwent radical compared with partial nephrectomy (6.8 cm vs 2.9 cm, P0.001). The rate of benign disease in our overall population was 9.5%. • On univariate and multivariate analysis, only a renal mass size2 cm and female gender were predictive of benign disease. On further analysis the magnitude of this effect was found to be additive.• Renal masses2 cm and female gender were associated with a higher probability of benign disease. • Patient age and tumour location were not predictive of benign disease.

it is associated with substantial peri-operative morbidity, which, despite advances in surgical and anesthetic technique, have remained relatively constant over the last decade. We sought to determine the impact of the robotic approach on 90 day peri-operative and short-term oncologic outcomes. METHODS: A robot assisted radical cystectomy (RARC) program was established at our institution in January 2008. Data was compiled prospectively in an institutional review board approved database. The Clavien system was used to report complications. A total of 124 patients have undergone RARC for bladder cancer from 20082011 and those with 90 day follow-up were included in this analysis. Data was retrospectively compiled on 100 consecutive patients that underwent ORC at our institution from 2005-2011. Uni& multivariate nominal logistic regression analysis was used to identify predictors of complications. RESULTS: A total of 100 ORC patients and 103 RARC patients had 90 days of follow-up and were included in this analysis. These patients did not differ in sex, age, BMI, previous abdominal surgery, radiation or systemic chemotherapy. More patients in the RARC group had an ileal conduit 97% vs 83% (p 0.03) and these procedures took longer, 451 min vs 393 min (P 0.0001). The RARC was associated with less blood loss, 423 cc vs 986 cc (P 0.0001), less need for blood transfusion, 15% vs 47% (P 0.0001) and decreased median length of stay, 6 vs 8 days (P 0.0001), when compared to ORC. RARC patients had less overall 35% vs 57% (P 0.0013) and major (Clavien 3), 10% vs 22% (p 0.0187) complications than ORC patients. In multivariate regression analyses, RARC was associated with a 65% decreased likelihood of any and a 68% decreased likelihood of a major complication (OR 0.35, p 0.001 and 0.32, p 0.001 respectively). No differences in short-term pathologic outcomes (pathologic stage, positive nodes, lymph node yield and positive margin rate) were noted. CONCLUSIONS: RARC is a safe procedure with benefits of reduced length of stay and decreased transfusion rates. Further gains with respect to overall and major complication rates were demonstrated in this cohort. Short-term oncologic outcomes were comparable to ORC. This large comparative series is encouraging and validates some findings of other groups and extends others suggesting the potential benefit of the robotic approach.

pT1 bladder urothelial carcinomas represent a heterogeneous group of tumors with different biologic behaviors, and identifying the subset of tumors that carries a high risk of disease recurrence and progression is therefore important. We evaluated the prognostic significance of substaging 86 cases of pT1 bladder urothelial carcinoma based on different pathologic parameters. The mean tumor depth was 1.1 mm, and the mean diameter of the invasive focus was 2.2 mm. The mean number of tissue fragments with invasion was 4.4. Lymphovascular invasion and concomitant carcinoma in situ were present in 13% and 45% of cases, respectively. Although 56% of patients recurred, 18% experienced disease progression. Multivariate analysis showed a significant association between muscularis mucosa invasion (P = .007), depth of invasion (P = .0001), diameter of invasive focus (P = .014), and progression. Furthermore, depth of invasion more than 3 mm was significantly associated with progression of disease, achieving a sensitivity of 31%, specificity of 99%, and predictive value of 79%. In comparison, the cutoff values for the diameter of invasive carcinoma that correlated best with outcome was 6 mm for progression. Lastly, combining both variables showed a strong prognostic accuracy where it predicted 94% of recurrences. Importantly, all cases with depth of invasion more than 3 mm and diameter more than 6 mm progressed. Lymphovascular invasion or concomitant carcinoma in situ did not correlate with outcome. From the current data, we do recommend reporting muscularis mucosa invasion whenever possible. Alternatively, tumor depth and tumor diameter should be included in the final pathology report in individual cases in which muscularis mucosa invasion cannot be assessed.

The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason-grade hormone-sensitive prostate cancer (P

Background. Prostate adenocarcinoma is predominantly a disease of older men. Males younger than 50 years account for 1% of all patients with prostate cancer. The authors retrospectively examined cases of prostate adenocarcinoma in patients younger than 50 years of age to determine the natural history and prognosis of this malignancy in the younger population. Methods. The medical records of 151 patients were reviewed, with particular attention to age and year at diagnosis, race, symptoms at presentation, family history of prostate cancer, histologic grade, clinical and pathologic stage, treatment modality, and clinical outcome. Results. Univariate analyses demonstrated a significant correlation between higher disease stage (P = 0.0001), higher tumor grade (P = 0.0001), earlier year of diagnosis (P = 0.01), symptoms at presentation (P = 0.0001), and race (P = 0.01) with shorter disease-specific survival. However, multivariate analysis revealed that only stage and grade were statistically significant predictors for poor prognosis after controlling for other variables. With a one-unit increase of stage or grade, the risk of death from disease increases 2.2 or 1.9 times, respectively. Conclusion. These data suggest that patients younger than 50 years with prostate cancer present with similar symptomatology, histologic grade, and disease stage as the older population. Patients with disease confined to the prostate have a relatively good disease-specific survival but remain at risk for death even 15 years after diagnosis When carcinoma escapes the confines of the prostate, the prognosis is uniformly poor.

We evaluated the value of the ‘alternative slices mirror image method’ used in prostate tissue banking in terms of predicting the sampling of cancerous tissue while preserving the pathological prognostic information. The concordance of diagnosis between banked sections and their mirror image paraffin- sections was studied using 50 cases corresponding to 400 H&E sections taken from 400 banked frozen blocks (two presumed benign and two presumed cancer for each case). The mean number of paraffin blocks in each case was 21. On average 29% of the prostate gland was banked and banked tissue contained cancer in 47 cases (94%). There was no difference between the concordant and discordant groups in terms of the final Gleason score, pathological stage, prostate size, number of banked blocks and the percentage of the prostate submitted for banking. However, concordant cases had larger foci of cancer in the mirror image paraffin block (P = 0.0088). In addition, the surgical margins sections which are not banked using this method provided important information about the pathological stage, surgical margins status and the final Gleason score in 2.6, 2.6, and 1.3% of cases, respectively. The ‘alternative slices mirror image method’ is a straightforward method that is highly efficient in banking prostatic cancerous tissue. Overall, tumor volume and especially size of tumor foci in the image paraffin block are the most important factors in dictating the success rate of banking frozen cancerous tissue. Including ‘surgical margins’ sections for histology provides additional important prognostic information in a minority of cases.

To assess outcome in patients with T1 high-grade (T1HG) bladder cancer treated at a single academic institution and to determine the prognostic factors that can help in counselling patients towards early cystectomy.Records of 2570 patients with bladder cancer treated from 1995 to 2005 were reviewed. Only patients diagnosed with T1HG disease were included in the analysis. Collected variables included various clinicopathological parameters, use of statins, smoking, as well as dates of recurrence, progression, radical cystectomy and death. Recurrence-free survival (RFS) and worsening-free survival (WFS) were analyzed. Multivariate Cox proportional regression analysis was employed to verify the prognostic significance of various variables.In total, 278 (10.8%) patients were identified as having T1HG disease on transurethral resection. 66% of patients who recurred, and 36.3% developed stage progression after a median (range) follow-up of 3 (0.1-15.4) years. 30% patients who underwent radical cystectomy, and 9% were dead of disease. The 5-year RFS and WFS rates were 26.6% and 49.4%, respectively. On multivariate analysis, only non-trigonal tumour location, restaging transurethral resection, history of previous carcinoma not invading bladder muscle and adjuvant bacille Calmette-Guérin (BCG) therapy were significantly associated with prolonged RFS, whereas papillary tumour architecture, history of previous carcinoma not invading bladder muscle and adjuvant BCG therapy were significantly associated with prolonged WFS.Patients with T1HG bladder cancer are at a significant risk of progression and death from disease. Primary tumours, sessile architecture and trigonal location are factors associated with a worse outcome and may be used to counsel patients towards early cystectomy.

Objectives The role of advanced age as an independent prognostic factor for clinical outcomes after radical cystectomy is controversial. The objective of the current study was to assess the associations between age and clinical outcomes in a large, multi-institutional series of patients treated with radical cystectomy for bladder cancer. Materials and methods Institutional radical cystectomy databases containing detailed information on bladder cancer patients treated between 1993 and 2008 were obtained from 8 academic centers in Canada. Data were collected on 2,287 patients and combined into a relational database formatted with patient characteristics, pathologic characteristics, recurrence status, and survival status. Patient age was coded as

Intrinsic oxidative stress through enhanced production of reactive oxygen species (ROS) in prostate and other cancers may contribute to cancer progression due to its stimulating effect on cancer growth. In this study, we investigate differential responses to exogenous oxidative stimuli between aggressive prostate cancer and normal cell lines and explore potential mechanisms through interactions between cytotoxicity, cellular ROS production and oxidative DNA damage. The circular, multi-copy mitochondrial DNA (mtDNA) is used as a sensitive surrogate to oxidative DNA damage. We demonstrate that exogenous H 2 O 2 induces preferential cytotoxicity in aggressive prostate cancer than normal cells; a cascade production of cellular ROS, composed mainly of superoxide (O 2 − ), is shown to be a critical determinant of H 2 O 2 -induced selective toxicity in cancer cells. In contrast, mtDNA damage and copy number depletion, as measured by a novel two-phase strategy of the supercoiling-sensitive qPCR method, are very sensitive to exogenous H 2 O 2 exposure in both cancer and normal cell lines. Moreover, we demonstrate for the first time that the sensitive mtDNA damage response to exogenous H 2 O 2 is independent of secondary cellular ROS production triggered by several ROS modulators regardless of cell phenotypes. These new findings suggest different mechanisms underpinning cytotoxicity and DNA damage induced by oxidative stress and a susceptible phenotype to oxidative injury associated with aggressive prostate cancer cells in vitro .

Objective To advise urologists and other clinicians on the appropriate management of low-stage (clinical Stage [CS] I, IS, IIA, and IIB) nonseminomatous germ cell tumors of the testis. Methods A panel was convened of experts from 5 countries. A literature search in MEDLINE was used to identify evidence from relevant studies on the outcome and toxicity of observational, surgical, and chemotherapeutic approaches for low-stage nonseminomatous germ cell tumors to form the basis of the panel's recommendations. Results The panel has recommended the treatment of nonseminomatous germ cell tumors in centers with medical, surgical, and diagnostic expertise in testicular cancer. The cancer-specific survival rate for CS I and CS IIA-IIB should approach 100% and 95%-100%, respectively. Patients with CS I should be made aware of all treatments (ie, surveillance, primary chemotherapy, and retroperitoneal lymph node dissection) and the potential side effects. For patients with CS I at low risk of occult metastasis, surveillance is preferred. For patients at high risk of occult metastasis, all 3 options can be considered. For immediate treatment, the choice between primary chemotherapy and retroperitoneal lymph node dissection should be determined by patient preference and the specific expertise of the treating institution. Patients with increasing postorchiectomy serum α-fetoprotein or human choriogonadotropin levels (CS IS and CS IIA-IIB) should receive induction chemotherapy. Induction chemotherapy or retroperitoneal lymph node dissection can be considered for patients with CS IIA-IIB with normal postorchiectomy α-fetoprotein and human choriogonadotropin levels. Surveillance can be considered for patients with equivocal computed tomography retroperitoneal findings who are otherwise at low risk of metastatic disease. Conclusion These clinical practice guidelines are designed to improve clinical practice from the available evidence and the expert opinion of the panel. As such, deviation from these recommendations should be based on sound clinical judgment, considering the unique situation of the patient and the expertise of the treating physician and institution.

Background. Although hormonal manipulation is standard therapy for patients with metastatic prostatic cancer, its use in localized disease in combination with surgical extirpation of the gland has not been investigated thoroughly and systematically. Methods. The authors report their initial pilot studies using preoperative neoad2j1uvant endocrine therapy. Results. Although marked reduction in serum prostate-specific antigen (PSA) levels occurred in all patients, the PSA level after endocrine manipulation did not predict the pathologic stage

Background Despite strong laboratory evidence that non-steroidal anti-inflammatory drugs (NSAIDs) could prevent prostate cancer, epidemiological studies have so far reported conflicting results. Most studies were limited by lack of information on dosage and duration of use of the different classes of NSAIDs. Methods We conducted a nested case-control study using data from Saskatchewan Prescription Drug Plan (SPDP) and Cancer Registry to examine the effects of dose and duration of use of five classes of NSAIDs on prostate cancer risk. Cases (N = 9,007) were men aged ≥40 years diagnosed with prostatic carcinoma between 1985 and 2000, and were matched to four controls on age and duration of SPDP membership. Detailed histories of exposure to prescription NSAIDs and other drugs were obtained from the SPDP. Results Any use of propionates (e.g., ibuprofen, naproxen) was associated with a modest reduction in prostate cancer risk (Odds ratio = 0.90; 95%CI 0.84-0.95), whereas use of other NSAIDs was not. In particular, we did not observe the hypothesized inverse association with aspirin use (1.01; 0.95–1.07). There was no clear evidence of dose-response or duration-response relationships for any of the examined NSAID classes. Conclusions Our findings suggest modest benefits of at least some NSAIDs in reducing prostate cancer risk.

Background Retroperitoneal lymph node dissection has been advocated for the management of post-chemotherapy (PC-RPLND) residual masses of non-seminomatous germ cell tumors of the testis (NSGCT). There remains some debate as to the clinical benefit and associated morbidity. Our objective was to report our experience with PC-RPLND in NSGCT. Methods We have reviewed the clinical, pathologic and surgical parameters associated with PC-RPLND in a single institution. Between 1994 and 2008, three surgeons operated 73 patients with residual masses after cisplatin-based chemotherapy for a metastatic testicular cancer. Patients needed to have normal postchemotherapy serum tumor markers, no prior surgical attempts to resect retroperitoneal masses and resectable retroperitoneal tumor mass at surgery to be included in this analysis Results Mean age was 30.4 years old. Fifty-three percent had mixed germ cell tumors. The mean size of retroperitoneal metastasis was 6.3 and 4.0 cm, before and post-chemotherapy, respectively. In 56% of patients, the surgeon was able to perform a nerve sparing procedure. The overall complication rate was 27.4% and no patient died due to surgical complications. The pathologic review showed presence of fibrosis/necrosis, teratoma and viable tumor (non-teratoma) in 27 (37.0%), 30 (41.1%) and 16 (21.9%) patients, respectively. The subgroups presenting fibrosis and large tumors were more likely to have a surgical complication and had less nerve sparing procedures. Conclusion PC-RPLND is a relatively safe procedure. The presence of fibrosis and large residual masses are associated with surgical complications and non-nerve-sparing procedure.

Background The TMPRSS2:ERG fusion is both prevalent and unique to prostate cancer (PCa) and has great potential for noninvasive diagnosis of PCa in bodily fluids. Objectives To evaluate the specificity and sensitivity of the TMPRSS2:ERG fusion in urine from diverse clinical contexts and to explore potential clinical applications. Design, setting, and participants A total of 101 subjects were enrolled in 2008 from urologic oncology clinics to form three study groups: 44 PCa free, 46 confirmed PCa, and 11 negative prostate biopsies. The PCa-free group included females, healthy young men, and post–radical prostatectomy (RP) patients. The confirmed PCa group was composed of patients under active surveillance, scheduled for treatment, or with metastatic disease. Measurements Urine was collected after attentive digital rectal exam (DRE) and coded to blind group allocation for laboratory test. RNA from urine sediments was analyzed using a panel of four TMPRSS2:ERG fusion markers with quantitative polymerase chain reaction (qPCR). Results and limitations Our fusion markers demonstrated very high technical specificity and sensitivity for detecting a single fusion-positive cancer cell (VCaP) in the presence of at least 3000 cells in urine sediments. In clinical analysis, there were no fusion-positive samples in the PCa-free group (0 of 44 samples), while there were 16 of 46 (34.8%) fusion-positive samples in the confirmed PCa group. The fusion incidence varied significantly among the three PCa subgroups. The clinical sensitivity increased to 45.4% in cancer patients prior to treatments. The fusion markers were detected in 2 of 11 (18.2%) biopsy-negative patients, suggesting potentially false negative biopsies. This study is not prospective and is limited in sample sizes. Conclusions Our novel panel of TMPRSS2:ERG fusion markers provided a very specific and sensitive tool for urine-based detection of PCa. Theses markers can potentially be used to diagnose patients with PCa who have negative biopsies.

The diagnosis and treatment of prostate cancer have steadily been improving since the late 1980s. However, clinicians still confront a large group of men developing disease metastatic to bone. Adequate control of bone complications plays a fundamental role in achieving control of symptoms and quality of life in this group. Androgen deprivation therapy, the standard treatment for advanced prostate cancer, increases the risk of various complications, including bone disease. This review addresses the prevention of bone complications related not only to prostate cancer metastases but also to impaired bone integrity caused by androgen deprivation therapy.

The association between use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of prostate cancer remains controversial despite many observational epidemiological studies. We conducted a systematic meta-analysis of these studies to examine both the strength and the consistency of the association, and to explore sources of variability between studies. We searched 12 computerized literature databases for reports published before June 2008 and included any epidemiologic studies where the outcome was prostate cancer incidence or mortality, and the exposure was use of NSAIDs. Studies that met the inclusion criteria comprised 10 case-control and 14 cohort studies with a total of 24,230 prostate cancer cases. Studies that assessed the effect of aspirin use on total prostate cancer had a pooled odds ratio (POR) of 0.83 (95%CI: 0.77-0.89), whereas those that assessed the effect of aspirin on advanced prostate cancer had a POR of 0.81 (0.72-0.92). Studies that examined the effects of non-aspirin NSAIDs or all NSAIDs were less consistent but still suggestive of reduced risks. However, most reviewed studies were limited by exposure and disease misclassification, by inadequate information on dose and duration of use and by the possibility of screening and other biases. In conclusion, the epidemiologic evidence for a protective effect of aspirin and other NSAID use against prostate cancer is suggestive but not conclusive. There is a need for well-designed observational studies with adequate exposure measurements, accurate case definition, attention to latency effects, and careful adjustment for screening and other biases.

Androgen ablation using hormonal manipulation is used extensively in metastatic prostate cancer; however, its use in localized disease combined with surgical extirpation of the gland has not been thoroughly and systematically investigated. The rationale for neoadjuvant therapy stems from the demonstrated effectiveness of androgen ablative therapy in metastatic disease and the high rate of "positive" surgical margins, especially in patients with Stage B2 disease. In addition, the essentially anecdotal clinical report of Scott and Boyd [1], using endocrine therapy plus radical prostatectomy in patients with Stage C disease, gives 15 year survival results comparable to those obtained by Jewett [2] in Stage 1 patients treated by radical prostatectomy. Finally, experimental observations in the androgen-sensitive mammary tumor (Shionogi) lend support to the concept of neoadjuvant hormonal manipulation. A pilot study of neoadjuvant endocrine therapy in 55 patients treated at Memorial Sloan-Kettering Cancer Center with 3 months of diethylstilbestrol (DES) (3 mg/day) prior to radical prostatectomy indicates marked reductions in prostate-specific antigen (PSA), although persistent evidence of adverse local tumor features was common. Some patients, however, exhibited evidence of significant downstaging. Whether or not any alteration in disease progression will accrue from demonstrated local downstaging is, of course, uncertain. However, clinical and laboratory effects of such treatment may provide a means for correlation with subsequent tumor behavior, and may prove useful in treatment decisions. Additionally, a decrease in the number of foci of grade 3 prostatic intraepithelial neoplasia (PIN-3) was noted in a small number of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Radical cystoprostatectomy with bilateral pelvic lymphadenectomy and urinary diversion remains the gold standard therapy for localized bladder cancer in men.1 The procedure has been refined over several decades with the current application of nerve-sparing techniques.2,3 Unfortunately, the procedure carries significant risks of urinary and sexual dysfunction resulting in bladder-sparing approaches being popularized for selected early invasive bladder cancers. More recently, some authors have suggested that prostate-sparing cystectomy may be appropriate in selected men to improve postoperative sexual and urinary function.4–6 They propose that leaving the prostate, or part of it, intact will result in less damage to pelvic innervation and better preservation of sexual function and urinary sphincter control in cases of orthotopic diversion. These potential functional improvements must be weighed against any risks for oncologic outcomes. One potential oncologic pitfall is the assumption that the prostate does not harbour transitional cell carcinoma (TCC) of the bladder. The incidence of occult prostatic involvement with TCC in patients undergoing radical cystectomy ranges between 20% and 48%,7–9 raising significant concern about sparing the prostate. In a large study, Pettus and colleagues10 concluded that patients with tumours involving the trigone and bladder neck or associated carcinoma in situ of the bladder should be considered at high risk for developing prostatic urethral carcinoma. Moreover, the absence of these factors did not conclusively rule out the presence of carcinoma in the prostatic urethra. Another significant risk is the potential for prostatic adenocarcinoma. Many argue that prostate cancer is not a major problem in this population, since men undergoing cystectomy for invasive bladder cancer are often elderly, with a poor prognosis for their bladder cancer. However, prostate-sparing surgery is usually offered to men whose pelvic disease is not advanced and in whom sexual function is normal, thus younger men. It is precisely in these younger men with early forms of invasive bladder cancer that occult prostate cancer could pose problems in the future. Occult prostate cancer has a reported incidence of 23% to 47% in men undergoing radical cystectomy. Furthermore, about 50% of these cancers are potentially significant based on histologic criteria.11–14 Revelo and colleagues11 detected that 41% of cases had unsuspected prostatic cancer, of which 48% were clinically significant and 16% were extracapsular. Of importance, 60% involved the apex, including 79% of significant cases, suggesting that recommending apical sparing as a compromise could potentially be equally hazardous. These findings were confirmed by another study in which 27% of patients undergoing cystectomy for invasive TCC of the bladder were found to have prostatic carcinoma (PCa), with 33% involving the apex of the prostate.15 The authors suggested that the high likelihood of apical prostate cancer requires careful excision of the apical margins. Kablain and colleagues13 previously reported that 38% of patients undergoing cystectomy for bladder cancer and who harbour prostate carcinoma had a distinct apical predominance of the tumours. In a recent study, Hautmann and colleagues16 addressed the probability of overlooking clinically significant prostate cancer using sextant biopsy. They analyzed specimens from 133 consecutive patients undergoing cystoprostatectomy for bladder cancer. Patients were included in the study if they had serum prostate-specific antigen (PSA) 25%. Systematic sextant biopsy was performed in the operating room immediately following cystoprostatectomy and prostates were subsequently step-sectioned (3 mm). The threshold defined to distinguish between significant and insignificant cancer was 0.5 cm3. Incidental prostatic cancer was found in 58 of the 133 bladder cancer patients (44%), with presence of significant cancer in many. Sextant biopsy detected 7 cancers, including 4 of 47 (9%) that were insignificant and 3 of 11 (27%) that were significant. Thus, sextant biopsy missed 8 (73%) of 11 of significant prostate cancers. These data suggest that despite careful screening for prostate cancer for cystoprostatectomy patients, it remains regularly overlooked in a significant proportion of clinically relevant cases. In a recent prospective study by Saad and colleagues,17 425 men had radical cystoprostatectomy for invasive bladder cancer and entire mounted prostates were step-sectioned at 2 to 3 mm intervals. Of 425 cases examined, there was histological evidence of prostatic adenocarcinoma in 90 cases (21.2%). Prostatic TCC was found in 66 patients (15.6%). There was also significant benign prostatic hyperplasia in 175 (41.2%). They concluded that the marginal reported functional advantage of prostate-sparing cystectomy is not worth the potential oncological risks. In a prospective study, Koraitim and colleagues18 studied urinary continence and voiding differences between men undergoing classic radical cystoprostatectomy and men with prostate-sparing cystectomy. They found no statistical difference between both groups with respect to urinary continence, but found a significant difference in peak flow rate. They concluded that preservation of prostatic apex may present an element obstructing the evacuation of ileal bladders.

The “atypical urothelial cell” cytologic category is nonstandardized. We subclassify atypical cases to “atypical, favor a reactive process” or “atypical, unclear if reactive or neoplastic.” We evaluated the predictive significance of atypical cases by looking at their histologic follow-up. Among the 1,114 patients and 3,261 specimens included, 282 specimens had histologic follow-up. An atypical diagnosis did not carry a significant increased risk of urothelial neoplasia compared with the benign category. Although an “atypical unclear” diagnosis carried a higher rate of detection of high-grade cancer on follow-up biopsy in comparison with “atypical reactive” or “negative” diagnoses (26/58 [45%] vs 15/52 [29%] and 16/103 [15.5%], respectively), this difference was not statistically significant. These results suggest that dividing atypical cases into 2 categories based on the level of cytologic suspicion of cancer does not add clinically relevant information within the atypical category. They also raise the question of the significance of the atypical category altogether.

Purpose High–dose rate brachytherapy (HDRB) is frequently used as a boost to external beam radiation therapy (EBRT) in prostate cancer patients. With the increasing use of small planning target volume margins in EBRT, prostatic edema induced by HDRB can be a contributing factor to geometric miss when HDRB is performed before or during EBRT. We assessed prostate gland volumetric change after single-fraction HDRB and its impact on definition of treatment volume for EBRT. Methods and Materials Thirty-one consecutive patients with intermediate-risk prostate cancer treated with single-fraction HDRB (10 Gy) combined with hypofractionated EBRT were analyzed. A second CT scan was performed 7 days after HDRB, and images were coregistered with the planning CT scan that contained the original clinical target volume (CTV). The post-HDRB prostate CTV volume was compared with the original CTV by a single observer. Results All patients presented volumetric variation. In most cases (68%), the prostate increased in volume, whereas it decreased in 32%. The mean prostatic volume was 42.2 cc before HDRB and 43.6 cc after HDRB, representing a mean volume difference of 3.4%, ranging from −14.2% to 23.8% (p = 0.756). This difference is the result of mean changes of 0.6 mm (−6.1 to 6.6) in the anterior–posterior, 0.5 mm (−5.5 to 3.0) in the lateral, and 0.2 mm (−5.0 to 5.0) in the superior–inferior axes. Conclusions Although a nonsignificant volumetric change occurs after single-fraction HDRB, individual variations on specific axis could lead to important uncertainties during EBRT.

In this issue of CUAJ, Mayson and colleagues1 of the CUA Socioeconomic Committee report the results of a survey of Canadian urologists on the privatization of health care. Although one cannot make general conclusions regarding the collective opinion of Canadian urologists based on a 9-question survey with a 20% response rate, some interesting results were nonetheless observed. Of interest, more than half of the survey respondents were already receiving direct payment from patients for services; this indicates that many urologists already have a private component, albeit small, to their practice. It would be of interest to look at the proportion of private care a few years from now, since in several parts of the country the door has been opened to some private activities. More results show that 65% of respondents believe that Canadians should have the freedom to choose private health care; in contrast, almost 20% feel that private health care should not be allowed at all. What is of further interest is that most respondents (74%) believe that the presence of a parallel private system would not adversely affect the health of patients treated in the public system; at the same time 58% believe that the health of patients in the private system would improve. Essentially, many of the respondents felt that allowing privatization would improve the health of those who can afford it and not improve the health of patients in the public system. This view is somewhat contrary to the views of those who promote privatization and who argue that the public system would be relieved of some expenses, and that privitization would thus improve access and care in the public system. As stated in the article, the eventual objective of the CUA Socioeconomic Committee is to develop a policy regarding privatization similar to other Canadian and provincial medical associations. It is unfortunate that this first attempt to gather opinions was inadequate, as only a fraction of members completed the survey. Notwithstanding this first attempt, more effort should be made to collect the opinions of urologists, to have a better understanding of our position as a whole. However, to understand this collective opinion, a constructive debate before canvassing their opinions would be helpful. Also, some advocates of privatization have proposed that certain procedures should not be universally covered in order to relieve the public system. It would be interesting to survey Canadian urologists to see what procedures they would advocate being removed from the public system. Finally, it is quite interesting to observe the debate occurring in the United States about their moving toward a Canadian-type model while we simultaneously debate moving in the opposite direction. Like most things in life, a moderate central position is often the right one.

OBJECTIVE To evaluate our experience with surgical resection of renal cell carcinoma (RCC) with inferior vena cava (IVC) involvement and examine the relationship between prognosis and tumour extent. PATIENTS AND METHODS A retrospective review of nephrectomy performed between 1985 and 2005 identified 50 patients presenting with tumour thrombus extension into the IVC. Clinical characteristics and outcome were evaluated. RESULTS Of the 50 patients evaluated, 7, 26, 10 and 7 presented with level I, II, III and IV thrombus, respectively. Major postoperative complications occurred in 16% of patients. Local or distant failure occurred in 25 (64%) patients. The mean time to recurrence was 10 months. Only supra-diaphragmatic extension of the tumour thrombus was predictive of disease recurrence. CONCLUSION Locally advanced RCC with IVC thrombus remains associated with significant local and distant failure rate. The level of thrombus extension is significantly associated with disease recurrence. Effective adjuvant therapy is needed to improve outcome in this patient population.

Urinary retention is common after anesthesia and surgery, reported incidence of between 5% and 70%. Comorbidities, type of surgery, and type of anesthesia influence the development of postoperative urinary retention (POUR). The authors review the overall incidence and mechanisms of POUR associated with surgery, anesthesia and analgesia. Ultrasound has been shown to provide an accurate assessment of urinary bladder volume and a guide to the management of POUR. Recommendations for urinary catheterization in the perioperative setting vary widely, influenced by many factors, including surgical factors, type of anesthesia, comorbidities, local policies, and personal preferences. Inappropriate management of POUR may be responsible for bladder overdistension, urinary tract infection, and catheter-related complications. An evidence-based approach to prevention and management of POUR during the perioperative period is proposed.

Ce numero du JAUC propose 3 articles tres interessants adoptant des approches technologiques tres differentes dans les cas du cancer de la prostate et du rein. Pourtant, chacune d’entre elles presente des objectifs tout a fait similaires : preservation des organes, therapie ablative a effraction minimale et moins de morbidites comparees aux therapies standards. Les progres rapides, en mesures ablatives percutanees dans le traitement du cancer en urologie, sont emballants. De telles modalites sont prometteuses, et en tres peu de temps, certaines d’entre elles sont aujourd’hui pretes a subir des tests. Actuellement, la plupart de ces nouvelles approches comportent 2 obstacles majeurs : une imagerie en temps reel et une localisation des cancers qui ne sont pas encore assez optimales, et un manque d’outils en imagerie moleculaire qui permettent de visualiser les caracteristiques des pronostics. Il serait dommage que les therapies ablatives, concues au depart pour les ablations completes d’organes in situ (comme dans le cas du cancer de la prostate), soient trop rapidement appliquees a la therapie focale ou a l’ablation d’une masse chez les hommes sans evaluation appropriee. Cependant, l’avancement en imagerie progresse tout aussi rapidement grâce au developpement des sondes microscopiques ou des traceurs marques pour illuminer les cibles. Un tout nouveau domaine d’imagerie moleculaire est en train d’emerger et nous ne pouvons pas nous permettre de manquer le bateau. Je suis confiant qu’a l’avenir, des images plus precises et de meilleurs pronostics ouvriront la voie a la chirurgie moleculaire. Nous suivrons avec empressement les rapports de suivi des auteurs impliques dans ce domaine stimulant. Il est important que les urologues maintiennent leur position de leadership dans la croissance de ces therapies guidees par l’image. Les urologues devraient se montrer plus actifs dans la mise au point d’outils d’imagerie, pour detecter la localisation des cancers et permettre des traitements plus precoces, de la meme maniere qu’ils le sont pour defendre l’utilisation des nouvelles therapies systemiques ciblees dans le cas des cancers urologiques. Il est clair que le chirurgien urologique, d’un futur pas si lointain, utilisera une combinaison de medicaments cibles, d’imagerie fonctionnelle et de systemes de livraison d’energie, bien plus que les DeBakey et Metz. Il y a une peinture a l’huile accrochee au mur dans mon bureau qui represente des chirurgiens en pleine chirurgie effractive. Apres en avoir admire sa beaute artistique, un patient s’est demande si l’on operait encore de cette facon. Je n’ai pas encore enleve la peinture!

Renal cell carcinoma (RCC) comprises approximately 2% of all malignancies. It is the seventh most common cancer and tenth most common cause of cancer-related deaths among men.1 Risk factors for RCC include smoking, obesity, and hereditary conditions associated with a mutation in the von-Hippel-Lindau gene (level 2).2,3 Surgical resection (radical or partial nephrectomy) remains the only effective therapy for clinically localized RCC. Publications that address surveillance after surgical extirpation are based on retrospective analysis, including some larger multicentre studies and well-designed controlled studies.4 Randomized prospective studies are sparse, rendering it difficult to obtain qualified evidence-based data. Although there is no clear consensus on surveillance after surgical extirpation for patients with RCC, this document attempts to provide some clarity and guidance for the practising urologist based on the current literature. Where possible, levels of evidence and grades of recommendations are provided employing the modified Oxford Centre for Evidence-based Medicine scheme.