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Objective To identify miRNA characteristic of metastatic clear cell renal cell carcinoma (ccRCC) and those indicative of cancer specific survival in nephrectomy and biopsy specimens. We also sought to determine if a miRNA panel could differentiate benign from ccRCC tissue. Materials and Methods RNA was isolated from nephrectomy and kidney biopsy specimens (n=156; n=46 respectively). Samples were grouped: benign, non-progressive and progressive ccRCC. MiRNA were profiled by microarray and validated by qRT-PCR. Biomarker signatures were developed to predict cancer status in nephrectomy and biopsy specimens. Cancer specific survival was examined using Kaplan-Meier and Cox proportional hazards analyses. Results Microarray analysis revealed 20 differentially expressed miRNA comparing non-progressive with progressive tumors. A biomarker signature validated in nephrectomy specimens had a sensitivity of 86.7% and a specificity of 92.9% for differentiating benign and ccRCC. A second signature differentiated non-progressive versus progressive ccRCC with a sensitivity of 93.8% and a specificity of 83.3%. These biomarkers also discriminated cancer status in biopsy specimens. Levels of miR-10a-5p, -10b-5p, and -223-3p were associated with cancer specific survival. Conclusion This study identified miRNA differentially expressed in ccRCC samples; as well as those correlating with cancer specific survival. Biomarkers identified in this study have the potential to identify patients who are likely to have progressive ccRCC, and although preliminary, these results may aid in differentiating aggressive and indolent ccRCC based on biopsy specimens. This article is protected by copyright. All rights reserved.

Objectives: To determine which risk factors are associated with overall survival in patients with T3b or T3c renal cell carcinoma. Materials and Methods: Retrospective chart review was performed on all patients who underwent a nephrectomy at Lahey Hospital from 1971-2014 and had a diagnosis of pathologic T3b or T3c renal cell carcinoma. Twenty-one potential risk factors were examined and analyzed using Cox Proportional Hazard Survival models. Additional factors examined in this cohort included rate of complications, tumor recurrence, intra-operative death rate, and 30-day mortality rate. Results: One-hundred eighty-two patients with stage T3b or T3c renal cell carcinoma met inclusion criteria. Of these, 124 (68%) were stage T3b and 58 (32%) were stage T3c. Median follow-up was 18.5 months. One-hundred and six (58%) patients experienced a complication from surgery. The intra-operative death rate was 1.1% (2 patients). The 30-day mortality rate was 7.1% (13 patients). Seventy-one (39%) patients had disease recurrence at a median of 7 months (range 1 - 232 months). The 5-year disease-specific survival was 40% and the 5-year overall survival was 32%. Of the 21 risk factors analyzed, clear cell histology, positive lymph nodes, and peri-nephric fat involvement were all significant at the p 0.05 level using unadjusted modeling. On multivariable analysis, fully adjusting for all three significant variables, only positive lymph nodes and peri-nephric fat involvement remained significant. Conclusions: In patients with T3b or T3c renal cell carcinoma overall survival is associated with lymph node positivity and peri-nephric fat involvement and not tumor thrombus level.

The data in the literature are confusing and conflicted as to the role of various surgical maneuvers and their impact on postoperative renal function. The aim of this chapter is to review the current literature and to present my own personal experience, regarding the role of warm ischemia and the volume of renal parenchyma preserved on the ultimate postoperative renal functional outcome following partial nephrectomy (PN).

High risk prostate cancer requires a multimodal approach to treatment. Surgery has played an increasing role for these patients although long-term follow-up and experience with neoadjuvant therapy, a basic tenet of cancer treatment, remains limited. Here we report our experience with neoadjuvant hormonal ablation followed by surgery and postoperative radiation with greater than 20-year follow-up. From 1990-2012, 82 patients with clinically organ-confined prostate cancer and 10 years median follow-up underwent multimodal therapy (MMT) consisting of neoadjuvant hormonal ablation followed by radical retropubic prostatectomy and postoperative radiation. High-risk prostate cancer was defined preoperatively as Gleason Score 8-10 or PSA>20. Patients with negative surgical margins were observed initially and treated with salvage XRT in the instance of recurrence. The MMT protocol was well tolerated in all 82 patients with no treatment-related discontinuation of therapy. Final surgical pathology revealed stage pT3-T4 in 58/82 (71%) and nodal involvement in 7/82 (9%). Distant metastatic disease was identified in 10/82 patients (12%). For patients undergoing MMT at 10, 15 and 20 years, cancer-specific survival was 78/82 (95%), 77 /82 (94%) and 77/82 (94%), overall survival was 68/82 (83%), 66/82 (80%) and 60/82 (73%), and biochemical recurrence was 61/82 (74%), 51/82 (62%) and 35/82 (43%). These findings establish the MMT protocol as an effective treatment strategy for high-risk prostate cancer with excellent long-term cancer-specific survival. Recurrence occurring primarily as a rising PSA as opposed to distant metastatic disease suggests limited morbidity as well among patients treated with this protocol.

Background Renal cell carcinoma forming a venous tumor thrombus (VTT) in the inferior vena cava (IVC) has a poor prognosis. Recent investigations have been focused on prognostic markers of survival. Thrombus consistency (TC) has been proposed to be of significant value but yet there are conflicting data. The aim of this study is to test the effect of IVC VTT consistency on cancer specific survival (CSS) in a multi-institutional cohort. Methods The records of 413 patients collected by the International Renal Cell Carcinoma–Venous Thrombus Consortium were retrospectively analyzed. All patients underwent radical nephrectomy and tumor thrombectomy. Kaplan–Meier estimate and Cox regression analyses investigated the impact of TC on CSS in addition to established clinicopathological predictors. Results VTT was solid in 225 patients and friable in 188 patients. Median CSS was 50 months in solid and 45 months in friable VTT. TC showed no significant association with metastatic spread, pT stage, perinephric fat invasion, and higher Fuhrman grade. Survival analysis and Cox regression rejected TC as prognostic marker for CSS. Conclusions In the largest cohort published so far, TC seems not to be independently associated with survival in RCC patients and should therefore not be included in risk stratification models. J. Surg. Oncol. 2016;114:764–768. © 2016 Wiley Periodicals, Inc.

Introduction: The use of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA) is an adjunctive surgical technique that can be employed for the resection of renal cell carcinoma (RCC) with venous thrombus extension superior to the level of the hepatic veins. Median Sternotomy (MS) or Minimal Access (MA) incisions may be used to establish CPB during the resection of these extensive tumors. We review our experience with both incisional approaches and compareoperative details, perioperative complications, and recurrence free survival. Materials and Methods: From 1986 to 2012, 70 radical nephrectomies with concomitant inferior vena cava (IVC) thrombectomies were performed at our institution using MS (23 patients) and MA (47 patients) techniques. Preoperative patient characteristics, pathologic data, and organ specific postoperative complications and follow-up data were compared between groups. Estimates of overall and recurrence-free survival were constructed using Kaplan-Meier curves and compared using log-rank testing. Results: There were no significant differences with respect to patient demographics or preoperative comorbid conditions between the MA and MS groups. The MA group showed a significant reduction (p < 0.05) in the duration of postoperative mechanical ventilation, length of stay, operative time, and number of blood transfusions compared to MS patients. Overall and organ-system specific complications demonstrated a decreased incidence of wound infection (37.9% v. 12.5%, p = 0.0135) and sepsis (14.3% v. 0%, p = 0.0137) in patients undergoing MA approach. Perioperative mortality was significantly reduced in the MA group (30.4% v. 8.5% p = 0.0179). Recurrence-free survival in the MS group was 0.59 years and 1.2 years in the MA group (p = 0.06). Conclusions: Minimal access surgical approaches for CPB and DHCA during the resection of RCC with extensive tumor thrombus provide similar oncologic control with decreased duration of mechanical ventilation, length of stay and infection related complications. Our findings suggest that MA techniques provide significant advantages over MS.

Objectives: To study the effect of lymph node dissection (LND) at the time of nephrectomy and tumor thrombectomy on oncological outcomes in patients with renal cell carcinoma (RCC) and tumor thrombus. Patients and methods: The records of 1,978 patients with RCC and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1985 to 2014 at 24 centers were analyzed. None of the patients had distant metastases. Extent and pathologic results of LND were compared with respect to cancer-specific survival (CSS). Multivariable Cox regression models were used to quantify the effect of multiple covariates. Results: LND was performed in 1,026 patients. In multivariable analysis, the presence of LN metastasis, the number of positive LNs, and LN density were independently associated with cancer-specific mortality (CSM). Clinical node-negative (cN-) disease was documented in 573 patients, 447 of them underwent LND with 43 cN- patients (9.6%) revealing positive LNs at pathology. LN positive cN- patients showed significantly better CSS when compared to LN positive cN+ patients. In multivariable analysis, positive cN status in LN positive patients was a significant predictor of CSM (HR, 2.923; P = 0.015). Conclusions: The number of positive nodes harvested during LND and LN density was strong prognostic indicators of CSS, while number of removed LNs did not have a significant effect on CSS. The rate of pN1 patients among clinically node-negative patients was relatively high, and LND in these patients suggested a survival benefit. However, only a randomized trial can determine the absolute benefit of LND in this setting. Copyright (C) 2018 Elsevier Inc. All rights reserved.

Background: Microscopic vein invasion (MVI), with local destruction and invasion of the endothelium by tumor, is of controversial predictive value in renal cell carcinoma (RCC). Objective: To assess the impact of venous extension and wall invasion in RCC on survival. Design, setting, and participants: Data for 1023 RCC patients with vena cava thrombus treated with radical nephrectomy and complete tumor thrombectomy were collected within a prospectively maintained international consortium (1995-2012). Outcome measurements and statistical analysis: The Kaplan-Meier method and univariable and multivariable Cox regression analyses were used to assess the impact of MVI on cancer-specific survival (CSS). The main two variables of interest were microscopic renal vein wall invasion (MRVI) and microscopic vena cava wall invasion (MVCI). Results: MRVI was found in 725 cases (70.9%) and MVCI in 230 (22.5%). Patients with MRVI had larger tumors (p = 0.005), longer hospital stay (p< 0.001), higher clinical stage 0.039), higher Fuhrman grade (p = 0.028), and more frequent fat invasion. Presence of MVCI was associated with larger tumors (p< 0.001), longer hospital stay (p< 0.001), higher clinical stage (p< 0.001), lymph node involvement (p = 0.045), higher Fuhrman grade (p< 0.001), and higher thrombus level (p< 0.001). With median follow-up of 52 mo, overall 5-yr CSS was 57.4%. Multivariable analysis showed that presence of MRVI was an independent factor related to CSS (hazard ratio 2.24, 95% confidence interval 1.24-3.59, p = 0.006). The main limitation was the inability to report MVI percentages. Conclusions: Patients with MRVI experience significantly worse survival outcomes after radical nephrectomy and tumor thrombectomy. Consideration of MRVI at final pathology is appropriate to improve decision-making for risk-adapted follow-up. Patient summary: The behavior of locally advanced renal cell carcinoma (RCC) depends on clinical and pathologic factors. Analysis revealed that RCC patients with microscopic renal vein wall invasion experience significantly worse cancer-specific survival. Patients with microscopic renal vein invasion (MRVI) who undergo radical nephrectomy and tumor thrombectomy experience significantly worse cancer-specific survival than patients without MRVI. The presence of MRVI at final pathology should be taken into consideration to improve decision-making for risk-adapted follow-up.

Background Radical nephrectomy (RN) with/without (±) thrombus excision (ThE) is the undisputed standard treatment for kidney cancer (KC) with renal or caval thrombus (Th). However, partial nephrectomy (PN) ± ThE may be considered in rare cases due to imperative (I) indications. Objective To evaluate the efficacy of IPN ± ThE and to compare it with RN ± ThE for KC with Th. Design, setting, and participants Records of 2,549 patients undergoing surgery for KC with Th at 24 institutions between 1971 and 2014 were retrospectively reviewed. Outcome measurements and statistical analysis Primary outcomes were overall survival (OS) and cancer specific survival (CSS), renal function variation after surgery and complications. Secondary outcomes were predictors of OS and CSS for IPN cases. To reduce bias IPN group was matched with RN using a propensity score with greedy algorithm on the basis of age, gender, tumor size, TNM, and histology. Results and limitations Forty-two patients underwent IPN ± Th. All thrombi were ≥level I; 5 patients experienced Clavien ≥ 3 complications with 2 complications-related deaths. At 27.3 (interquartile range: 7.1–47.7) months OS and CSS were 54.8% and 78.6%, respectively whereas at 9.7 (interquartile range: 1.4–43.7) months eGFR change was −17.3 ± 27.0 ml/min. On univariate analysis tumour size, preoperative eGFR, transfusions, hospital stay, high serum creatinine, operating time, complications, lymphadenectomy, and metastases related to an increased risk of death. After matching (n = 38 per arm) no significant differences were present except for tumor necrosis (IPN = 39.5%; 15.8%; P = 0.01), thrombus level (P = 0.02), so as for operating time (P = 0.27), perioperative transfusions (P = 0.74) and complications (P = 0.35). A 5-year OS and CSS for IPN were 57.9% and 73.7%, respectively with no significant differences with RN (OS = 63.2, P = 0.611; CSS = 68.4, P>0.99). After 14.9 months creatinine and eGFR changes were (+0.4 ± 0.6 mg/dl and −23.2 ± 37.3 ml/min; P = 0.2879). Conclusions In selected cases due to imperative indications PN ± ThE is a complex procedure and may be an alternative to RN ± ThE for KC with Th yielding noninferior oncological outcomes, functional outcomes, and complications. Further studies are needed to determine the role of PN ± ThE for KC with Th.

The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3–T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease.

Objective To clearly define the proportions of benign vs malignant histologic findings in resected renal masses through an in-depth review of the contemporary medical data to assist in preoperative risk assessment. Materials and Methods PubMed and select oncology congresses were searched for publications that identify the histologic classification of resected renal masses in a representative sample from the contemporary data: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit 2003-2011. Results We identified 26 representative studies meeting the inclusion criteria and incorporating 27,272 patients. The frequency of benign tumors ranged from 7% to 33%, with most studies within a few percentage points of the mean (14.5% ± 5.2%, median 13.9%). Clear cell renal cell carcinoma occurred in 46% to 83% of patients, with a mean of 68.3% (median 61.3; SD = 11.9%). An inverse relationship between tumor size and benign pathologic features was identified in 14 of 19 (74%) studies that examined an association between tumor size and pathologic characteristics. A statistically significant correlation between clear cell renal cell carcinoma and tumor size was identified in 13 of 19 studies (63%). The accuracy of preoperative cross-sectional imaging was low in the 2 studies examining computed tomography (17%). Conclusion Benign renal tumors represent ∼15% of detected surgically resected renal masses and are more prevalent among small clinical T1a lesions. Noninvasive preoperative differentiation between more and less aggressive renal masses would be an important clinical advance that could allow clinicians greater diagnostic confidence and guide patient management through improved risk stratification.

We report a case of a 54-year-old patient with a T3c renal mass with intracardiac extension of the thrombus to the level of the pulmonary valve. The patient was not a candidate for cardiopulmonary bypass due to recent pulmonary embolism. Under transesophageal echocardiogram guidance, the intracardiac thrombus was removed percutaneously via transvenous mechanical thrombectomy. The patient was effectively downstaged to T3b and underwent successful radical nephrectomy and inferior vena cava thrombectomy without the use of cardiopulmonary bypass.

What's known on the subject? and What does the study add? LumagelTM is a reverse thermosensitive polymer (RTP) that has previously been described in the literature as providing temporary vascular occlusion to allow for bloodless partial nephrectomy (PN) while maintaining blood flow to the untargeted portion of the kidney. At body temperature, LumagelTM has the consistency of a viscous gel but upon cooling rapidly converts to a liquid state and does not reconstitute thereafter. This property has allowed for it to be used in situations requiring temporary vascular occlusion. Previous experience with similar RTPs in coronary arteries proved successful, with no detectable adverse events. We have previously described our technique for temporary vascular occlusion of the main renal artery, as well as segmental and sub-segmental renal branches, to allow for bloodless PN in either an open or minimally invasive approach. These experiments were performed in the acute setting. This study is a two-armed survival trial to assess whether this RTP is as safe as hilar clamping for bloodless PN. Surviving animals showed normal growth after using the RTP, absence of toxicity, no organ dysfunction, and no pathological changes attributable to the RTP. We conclude that LumagelTM is as safe as conventional PN with hilar clamping, while adding the advantage of uninterrupted perfusion during renal resection. OBJECTIVE • To examine whether randomly selected regions of the kidney could undergo temporary flow interruption with a reverse thermosensitive polymer (RTP), LumagelTM (Pluromed, Inc., Woburn, MA, USA), followed by partial nephrectomy (PN), without adding risks beyond those encountered in the same procedure with the use of hilar clamping. MATERIALS AND METHODS • A two-armed (RTP vs hilar clamp), 6-week swine survival study was performed. • Four swine underwent PN using hilar clamps, while six underwent PN with flow interruption using the RTP. • The RTP, administered angiographically, was used for intraluminal occlusion of segmental or subsegmental arteries and was compared with main renal artery clamping with hilar clamps. The resection site was randomized for each swine. • Laboratory studies were performed preoperatively, and at weeks 1, 3 and 6. • Before killing the swine, repeat angiography was performed with emphasis on the site of previous flow interruption. • Gross and microscopic examination of kidney, liver, lung, heart, skeletal muscle was later performed, and the vessel that had supported the previous plug was examined. RESULTS • All animals survived. No abnormal chemistry or haematology results were encountered over the 6 weeks. There were no surgical complications in either group. • Using angiography we found 100% patency of vessels that had been occluded with the polymer 6 weeks previously for PN. The only gross or microscopic abnormalities were related to the renal resection and scar formation, and were similar in the two groups. CONCLUSION • Targeted flow interruption with the RTP added no additional risk to PN while allowing bloodless resection and uninterrupted flow to untargeted renal tissue.

To determine whether reversible blood flow interruption to a randomly chosen target region of the kidney may be achieved with the injection of a reverse thermoplastic polymer through an angiographic catheter, thereby facilitating partial nephrectomy without compromising blood flow to the remaining kidney or adding risks beyond those encountered by the use of hilar clamping. Fifteen pigs underwent partial nephrectomy after blood flow interruption by vascular cross-clamping or injection of polymer (Lumagel™) into a segmental artery. Five animals were euthanized after surgery (three open and two laparoscopic resection, cross-clamping n = 2), and 10 (open resection, cross-clamping n = 4) were euthanized after 6 weeks’ survival. Blood specimens were obtained periodically, and angiogram and necropsy were performed at 6 weeks. Selective renal ischemia was achieved in all cases. Surgical resection time averaged 9 and 24.5 min in the open and laparoscopic groups, respectively. Estimated blood loss was negligible with the exception of one case where an accessory renal artery was originally overlooked. Reversal of the polymer to a liquid state was consistent angiographically and visually in all cases. Time to complete flow return averaged 7.4 and 2 min for polymer and clamping, respectively. Angiography at 6 weeks revealed no evidence of vascular injury. Laboratory data and necropsies revealed no differences between animals undergoing vascular clamping or polymer injection. Lumagel was as effective as vascular clamping in producing a near bloodless operative field for partial nephrectomy while maintaining flow to the uninvolved portion of the affected kidney.

Objective • To compare outcomes of hilar clamping and non-hilar clamping partial nephrectomy for tumours involving a solitary functional kidney. Patients and methods • Between 1990 and 2009, 104 partial nephrectomies, excluding bench and autotransplant procedures, were performed on solitary functional kidneys. • An institutional review board-approved retrospective review was performed analyzing patient demographics, operative data, complications, oncological outcomes and estimated glomerular filtration rate (GFR). • GFR was calculated using the abbreviated Modification of Diet in Renal Disease equation. • Preoperative GFR was compared to Early GFR (lowest measured GFR 7-100 days postoperatively) and to Late GFR (GFR 101-365 days postoperatively). • Multiple linear regression analysis was performed to assess covariates affecting Late GFR. • Kaplan-Meier estimator was utilized to compare renal cell carcinoma (RCC) specific survival and non-RCC-related survival. Results • In total, 29 partial nephrectomies with hilar clamping and 75 partial nephrectomies without hilar clamping were performed in solitary kidneys. Median follow-up was 57 months. • There was no difference in tumour size, location and the number of tumours resected between the two groups. Mean ischaemia time for the clamping group was 25 min. • Some 97% of the clamping procedures were performed with cold ischaemia. • There was no difference in intra-operative estimated blood loss, transfusion requirement or length of hospital stay. • The complication rate and spectrum of complications were similar between the two groups. • The two groups had similar preoperative GFR and Early GFR. The non-clamping group had a significantly smaller percent decrease in Late GFR (11.8% vs 27.7%, P= 0.01) than the clamping group. • The non-clamping group was significantly more likely to have a less than 10% decrease in Late GFR compared to the clamping group (60.9% vs 17.7%, P= 0.002). • On multivariate analysis, only hilar clamping was significantly associated with decreased Late GFR (estimate 15.0, P= 0.02). • Surgical margin positivity rate was higher in the clamping group (21% vs 4%, P= 0.01); however, the local recurrence rate between the two groups was similar. • The clamping and non-clamping groups had similar 5-year RCC-specific survival and 5-year non-RCC-related survival. Conclusions • Partial nephrectomy without hilar clamping in solitary kidneys provides similar cancer control compared to partial nephrectomy with hilar clamping. • Partial nephrectomy without clamping was associated with superior preservation of Late GFR. • No difference was detected in GFR early after surgery, possibly indicating that there may be ongoing renal loss after hilar clamping.

OBJECTIVE • To describe our technique of partial nephrectomy (PN) without vascular clamping with perioperative and short-term data to determine the safety, impact on renal function and oncological efficacy of this approach. PATIENTS AND METHODS • We performed a retrospective review of 952 PNs done at our institution between 1987 and 2009. Patients undergoing ex vivo PN with auto-transplantation, patients with Von Hippel-Lindau disease and patients with incomplete follow-up information were excluded from the analysis. • The four-variable modification of diet in renal disease equation was used to calculate estimated glomerular filtration rate (eGFR). • The percentage change in eGFR at 1 year was compared between the two groups. RESULTS • The analysed cohort comprised 116 PNs done with renal vascular clamping (group A) and 192 PNs done without clamping (group B). The median tumour size was slightly larger in group B than in group A (3.0 vs 2.8 cm, P = 0.002). • There was no difference in preoperative eGFR (P= 0.304) or the prevalence of solitary kidney (P= 0 . 69 ). • Median estimated blood loss was 300 mL higher in the unclamped group (P< 0.001) and was associated with a higher rate of transfusion (P= 0 . 001 ). There was no difference the positive margin rate or rate of recurrence (P = 0.60). • The median percentage change in eGFR was a 12.3% decrease for group A and a 9.8% decrease for group B at 1 year (P = 0.037). In the subset of patients with solitary kidneys, the median change in eGFR was a 21% decrease in group A and a 4.4% decrease in group B at 1 year (P = 0.027). • The rate of complications was similar in groups A and B (11.2 vs 9.9%, P= 0.72). There were no perioperative deaths. CONCLUSIONS • Partial nephrectomy can be safely performed without vascular clamping in appropriately selected patients. • Although PN without vascular clamping is associated with higher estimated blood loss, it is also associated with better preservation of renal function without compromising oncological efficacy, as evidenced by the solitary kidney cohort.

What’s known on the subject? and What does the study add? Epithelial-mesenchymal transition (EMT) is involved in tumor progression where the underlying cellular changes associated with EMT have been identified in in vitro models and confirmed in a limited number of in vivo studies. ZEB1, which targets E-cadherin repression, is a transcriptional regulator that has been implicated in EMT, and is associated with uterine and colorectal cancers. Regulation of ZEB1 expression has been shown to involve different microRNAs (miRNAs), identifying a potential role for miRNA in EMT. In the present study we have identified novel expression of ZEB1 in bladder tumours and shown a role for ZEB1 in enhanced migration and invasion potential in in vitro assays. Confirmation of ZEB1 expression in bladder tumours was shown in tissue microarrays (TMAs). OBJECTIVE To evaluate ZEB1 expression in bladder tumorigenesis and define a possible role for this transcription factor in urothelial carcinomas of the bladder (UCBs). MATERIALS and METHODS Five hundred and fifty-eight samples were assembled in 10 tissue microarrays (TMAs; 263 non-muscle-invasive Ta/T1/Tis, 295 muscle-invasive T2–T4). All tumours were transitional cell carcinomas (TCCs) and processed for immunohistochemistry to assess nuclear ZEB1 expression. Expression levels of ZEB1 were modulated in bladder carcinoma cell lines CUBIII or UM-UC-3 after forced expression or shRNA knockdown, respectively. Protein expression levels were determined using western blot analysis and transfectants were assessed for migration and invasion potential in standard in vitro assays. RESULTS Nuclear ZEB1 expression was recorded in 22.8% of non-muscle-invasive UCBs and 21.7% of muscle-invasive UCBs, including 24.1% grade I/II and 21.1% grade III tumours, and absent in normal bladder mucosa. No significant correlation was observed for tumour stage and grade, nodal involvement, vascular invasion, metastasis and overall or cancer-specific survival. The introduction or knockdown of ZEB1 expression in bladder carcinoma cell lines showed enhanced or reduced migration and invasive potential, respectively. Changes in ZEB1 expression were accompanied by altered microRNA (miRNA) expression underlying events linked to epithelial–mesenchymal transition (EMT). CONCLUSION The results in the present study showed novel expression of ZEB1 in bladder cancer in the absence of a link to clinical variables of change, including metastasis and survival. However, in vitro assays showed enhanced or reduced migration and invasion after the introduction or reduction of ZEB1, respectively, in transfected bladder cell lines. Modulation in expression of ZEB1 was closely linked to changes in the miR-200 family along with alternative known prognostic indicators of bladder tumour progression.

Given the steadily growing cancer survivor population, increasing pressure has been placed on more effective clinical approaches and biomarker assays to manage care. For bladder cancer despite the high probability of recurrence the number of patients with recurrent disease is significantly lower than the number that remains cancer free at any monitoring interval. We developed a noninvasive urine assay using a novel approach to identify patients without recurrent cancer with extremely high confidence.Previous studies show that matrix metalloproteinases are increased in the urine of patients with cancer compared to that in disease-free individuals. To determine the clinical usefulness of these markers as monitors for bladder cancer recurrence we measured and compared metalloproteinase-2, metalloproteinase-9 and metalloproteinase-9/neutrophil gelatinase-associated lipocalin by enzyme-linked immunosorbent assay and zymography in a set of 530 samples, including 84 samples from patients with bladder cancer.Initial studies using urine metalloproteinase to discriminate disease-free patients from those with bladder cancer resulted in 80% sensitivity (67 of 84) and 71% specificity (318 of 446) for metalloproteinase-9. By applying our novel Clinical Intervention Determining Diagnostic() clinical approach to metalloproteinase-9 we correctly identified 42% of cases that were cystoscopy negative with 98% negative predictive value.A noninvasive urine diagnostic assay that uses metalloproteinases with the Clinical Intervention Determining Diagnostic could lead to more efficient treatment in bladder cancer survivors by decreasing the number of negative cystoscopies (42%), allowing physicians to more selectively monitor those at high risk.

Introduction We compared the functional and anatomical differences among three different orthotopic neobladders, utilizing video urodynamics and 3D CT to determine what parameters, if any, correlate to function. Materials and Methods Thirty-four patients were able to participate in the evaluation of their neobladder by 3D CT and video urodynamics. Three different orthotopic neobladders were identified (12 ileal, 7 ileocecal, 15 sigmoid). Multiple measurements, observations and functional data have been obtained. Statistical analysis for this study employed a linear regression test and an odds ratio calculation (using StatSoft V. 5.1). Results In comparing three different neobladders, no significant differences were noted. Looking at the entire population, the following association was statistically significant in linear correlation: the maximal capacity and the neobladder volume; the pressure at the maximal capacity and the distance from the symphysis, the pressure at maximal flow and both the distance from the symphysis and the thickness of the neobladder. The distance from the left femoral head was directly correlated with the post void residual and inversely correlated with the maximal flow. The Odds ratio calculation revealed (with significant P

To identify changes associated with P-cadherin expression in bladder cancer and evaluate the potential role of such events in determining the clinical outcome and cell behaviour, as the function of P-cadherin in normal epithelium is unknown, as is its potential role in neoplastic progression in different cancers.In all, 536 bladder tumour specimens from 408 patients were assembled in seven tissue microarrays. Paraffin sections from each array were processed for immunohistochemistry to assess the expression of P-cadherin. The expression of P-cadherin was forced using lipofectin, followed by an assessment of migration and invasion potential using standard in vitro assays.The absence of P-cadherin staining was associated with muscle-invasive disease, grade 3 (P0.001) and nodal disease (P = 0.009). Similar results were obtained when considering cytoplasmic and unrestricted localization of P-cadherin (P0.001), except for nodal involvement. The group with cytoplasmic location of P-cadherin showed a shorter cancer-specific survival than the group with membrane location of P-cadherin (P = 0.03). Forced expression of P-cadherin in EJ and UM-UC-3 cells, that constitutively lack P-cadherin expression, resulted in modulation of catenin expression and enhanced migration of EJ and UM-UC-3/P-cadherin transfectants (200%).These results showed that loss of expression, cytoplasmic relocation or unrestricted tissue location of P-cadherin was associated with a poor clinical outcome and prognosis in bladder cancer. From the in vitro work it is evident that P-cadherin plays a role in regulating the migration potential of bladder carcinoma cells.

Surgical resection of renal cell carcinoma remains the mainstay for the management of patients who suffer from this disease. Five percent to 10% of renal cell carcinomas develop a tumor thrombus that propagates into the renal vein or the inferior vena cava. Radical nephrectomy and inferior vena cava thrombectomy can provide longstanding survival rates comparable to those for tumors confined to the renal parenchyma. In general the surgical approach is dictated by the cephalad extension of tumor thrombus. This article reviews the authors' experience with 243 patients who suffered from renal cell carcinoma with extension into the venous system with specific reference to the surgical techniques and the long-term outcomes.

The percentage of patients who had achieved continence in the control group were: 13%, 35%, 50%, 62% and 82% at the 1-, 6-, 12-, 24- and 52-week follow-up, respectively. The percentage of patients who had achieved continence in the anterior reconstruction group were 27%, 59%, 77%, 86%, and 91%, respectively. The total reconstruction group had continence rates of 38%, 83%, 91%, and 97% at 1, 6, 12, and 24 weeks, respectively. At all the follow-up intervals the continence rate was significantly less in the control group than in the anterior reconstruction group and the total reconstruction group ( P < 0.01).

We established the frequency of mutation of the epidermal growth factor receptor in bladder cancer and determined whether the activation status of epidermal growth factor receptor confers sensitivity to erlotinib.The identification of mutations in the kinase domain (exons 18-21) of epidermal growth factor receptor was performed using single strand conformation polymorphism. The action of erlotinib was established within a bladder carcinoma cell panel using clonogenic assays and Western blot analysis.In 112 invasive bladder tumors a total of 6 mutations in 4 patients (3.6%) were identified in exon 21. Erlotinib demonstrated concentration dependent inhibition of growth where three cell lines showed high and 2 showed low sensitivity to the drug. Erlotinib inhibited activation of epidermal growth factor receptor, mitogen activated protein kinase, Akt and STAT3. However, the activation status of Akt was maintained in cell lines that were insensitive to the inhibitory action of erlotinib and were characterized as having undergone epithelial-to-mesenchymal transition.Although mutations in the coding region of epidermal growth factor receptor are rare in invasive bladder tumors, differential sensitivity to erlotinib was recorded within a panel of cell lines. Maintenance of the phosphorylation status of Akt in the presence of erlotinib along with epithelial-to-mesenchymal transition correlates with insensitivity to growth inhibition in bladder carcinoma cell lines. Even in the absence of epidermal growth factor receptor mutations erlotinib shows potential as a therapeutic agent for the treatment of bladder cancer.

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)

RNA from cell-free urine was analyzed in an attempt to identify a microRNA (miRNA) profile that could be used as a non-invasive diagnostic assay to detect the presence of urothelial carcinoma of the bladder (UCB) and provide a discriminatory signature for different stages of progression. In addition, the presence of specific miRNAs co-isolating with urinary extracellular vesicles/exosomes was investigated. RNA was isolated from cell-free urine of patients diagnosed with UCB (TaG1, T1G3, ≥T2, CIS) and control patients (healthy control and UCB patients with no evidence of disease). MiRNAs were profiled by qRT-PCR array on pooled samples within each group. Validation of the miRNAs was performed on individual samples using qRT-PCR. Extracellular vesicles were isolated via ultracentrifugation. 236 miRNAs were detected in at least one of the pooled samples. Seven of the miRNAs validated on individual samples had significantly higher levels in the cancer group. A panel of miRNAs discriminated between cancer and cancer-free patients with a sensitivity of 88% and specificity of 78%, (AUC=88.8%). We recorded a sensitivity of 80% for TaG1, 95% for T1G3, 90% for ≥T2 with specificity of 77% for healthy controls and 80% for no evidence of disease. Select miRNAs were detected in extracellular vesicles of UCB patients and healthy controls, albeit at different levels. Utilizing this non-invasive assay, we identified miRNA capable of detecting UCB and distinguishing different stages of progression, providing evidence that miRNA profiling in cell-free urine holds promise for the development of valuable clinical diagnostic tools.

INTRODUCTION AND OBJECTIVES: Pathologic upgrading from biopsy to prostatectomy occurs in approximately 30% of prostate cancer cases. PSA, a nonspecific protein, has previously been the primary serum marker for prostate cancer. Markers that more accurately assess risk of aggressiveprostate cancer at the timeof screening are critical for the future management of this disease. The aim of this study was to identify a panel of microRNA (miRNA) from serum that could differentiate patients with low-risk (Gleason 6) prostate cancer on TRUS biopsy specimenswho were either the same grade or upgraded at the time of prostatectomy. METHODS: Total RNA was isolated from serum of patients who had Gleason Sum (GS) 6 prostate cancer at the time of TRUS guided prostate biopsy. These patients were divided into groups with GS 6 that remained GS 6 (same grade) at prostatectomy and those who were upgraded to GS7 (upgrade) at the time of prostatectomy. For the discovery phase, sample pools from each group were profiled via miRNA PCR array (Exiqon). Validation of miRNA expression levels was performed on 29 same and 31 upgrade samples by qRT-PCR. RESULTS: Array analysis of 751miRNA identified34miRNAwith 2-fold differential expression between patients who had Gleason upgrading between biopsies and prostatectomy compared to patients who were same grade. Of these, 20 miRNA were down-regulated and 14 were up-regulated in theupgradedgroup.Additionally, 3miRNAwereexpressed in the upgrade groupwhich were not detected in the same grade group. 17 miRNA were further validated by qRT-PCR on individual samples. miR425-5pandmiR-146-5pwere found tobesignificantlydifferent between the same grade and upgraded groups. ROC curve of logistic regression analysis of theses two showed an area under the curve of 0.691. CONCLUSIONS: Serum samples demonstrated different miRNA expression levels between samples that were same grade or upgraded from Gleason 6 at prostatectomy. This minimally invasive assay could provide an adjunct to PSA and prostate biopsies to better counsel patients on management of low-risk prostate cancer and monitor patients on active surveillance.

INTRODUCTION AND OBJECTIVES: Neoadjuvant chemotherapy prior to radical cystectomy has been shown to confer a survival advantage in patients with muscle-invasive bladder cancer. When combined with maximal endoscopic resection of visible tumor, 38% of patients can be rendered pathologic stage 0 (pT0) at the time of cystectomy. Previous studies have shown differential expression of microRNA (miRNA) in the cell-free urine of patients with muscle invasive and non-muscle invasive bladder cancer. We aimed to identify miRNA in the urine of patients with a history of invasive bladder cancer and differentiating patients with a complete response to therapy from those with persistent disease. METHODS: Total RNA was isolated from cell-free urine of patients undergoing cystectomy for muscle-invasive cancer (pT0, pT1, and >pT2), cT0 patients on active surveillance with a history of muscle invasive disease, as well as healthy control samples (HC) from patients with no history of cancer. Patient samples were divided into four groups: HC (n1⁄413), pT0/cT0 (n1⁄417), pT1 (n1⁄49) and pT2 (n1⁄423), consistent with the pathologic tumor stage of the specimen at the time of TURBT or surgery. Pooled RNA isolates from each group were profiled via PCR array of 751 miRNA (Exiqon). MiRNA expression levels were validated on individual samples by qRT-PCR. RESULTS: The number of miRNA detected within each group correlated with the severity of disease where 391 miRNAs were detected in the pT2 group, 137 in the pT1 group, 124 in the pT0/cT0 group, and 73 among the HCs. Hierarchical cluster analysis revealed two main branches; one consisting of the HC and pT0/cT0 pools and the other comprised of the pT1 and pT2 pools. Additionally, 32 miRNA were expressed in the pT1 and pT2 pools, and not detected in the pT0/ cT0 and HC pools. qRT-PCR confirmed differential expression of several miRNA distinguishing the two clustered groups (p

INTRODUCTION AND OBJECTIVES: The objective of this study were to investigate the genetic changes responsible for bladder cancer metastasis, using orthotopic metastatic mouse model, and to find new therapeutic targets of invasive bladder cancer. METHODS: Human UM-UC-3 bladder cancer cells were generated to express firefly luciferase 2 and red fluorescent protein tdTomato (UM-UC-3-tdTomato-luc2). Subsequently, we developed an orthotopic xenograft nude mouse model of bladder cancer by inoculating UM-UC-3-tdTomato-luc2 cells through a urethral catheter into the mouse bladder. We then performed bioluminescent imaging (BLI) to noninvasively monitor the growth of bladder tumors in their orthotopic sites. Two mice underwent autopsy after confirmation of lung or liver metastases using BLI. The primary and metastatic tumors were excised and plated on tissue culture dishes to generate bladder, lung, liver, and bone sublines. To examine the role of metastasis-related genes in bladder cancer, we then performed comparative microarray analyses of gene expression, and analyzed gene expression changes in bladder vs. lung, bladder vs. liver and bladder vs. bone. RESULTS: Among the 8 genes commonly up-regulated in metastatic sublines compared to bladder cells by our microarray analysis, the expression of aldo-keto reductase 1C1 (AKR1C1) was especially up-regulated. Furthermore, AKR1C1 was significantly upregulated in the 3 metastatic sublines by qRT-PCR and immunoblot analysis. In clinical samples, we observed increased expression of AKR1C1 in human metastatic tissues compared with the corresponding primary bladder cancer tissues by qRT-PCR and immunohistochemistry analysis. Knockdown of AKR1C1 using small interfering RNA downregulated expression levels of Rac1, phosphorylated Src, and phosphorylated FAK, accompanied by reduced invasive ability. Overexpression of AKR1C isoforms, including AKR1C1, has been demonstrated to be associated with drug resistance in various cancers. UM-CU-3 metastatic cells were more resistant to cisplatin than were UM-UC-3 wild-type cells, and AKR1C1 inhibitor flufenamic acid reversed cisplatin resistance in these cells. CONCLUSIONS: We found that AKR1C1 was up-regulated both in metastatic bladder cancer cells using an orthotopic mouse model and in metastatic sites of human surgical specimens. Our results demonstrate the role of AKR1C1 in regulating bladder cancer metastasis and drug resistance; therefore, AKR1C1 is a potential target for effective treatment of invasive bladder cancer.

Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival.The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates.Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival.In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

The impact of cardiopulmonary bypass in level III-IV tumor thrombectomy on surgical and oncologic outcomes is unknown. We determine the impact of cardiopulmonary bypass on overall and cancer specific survival, as well as surgical complication rates and immediate outcomes in patients undergoing nephrectomy and level III-IV tumor thrombectomy with or without cardiopulmonary bypass.We retrospectively analyzed 362 patients with renal cell cancer and with level III or IV tumor thrombus from 1992 to 2012 at 22 U.S. and European centers. Cox proportional hazards models were used to compare overall and cancer specific survival between patients with and without cardiopulmonary bypass. Perioperative mortality and complication rates were assessed using logistic regression analyses.Median overall survival was 24.6 months in noncardiopulmonary bypass cases and 26.6 months in cardiopulmonary bypass cases. Overall survival and cancer specific survival did not differ significantly in both groups on univariate analysis or when adjusting for known risk factors. On multivariate analysis no significant differences were seen in hospital length of stay, Clavien 1-4 complication rate, intraoperative or 30-day mortality and cancer specific survival. Limitations include the retrospective nature of the study.In our multi-institutional analysis the use of cardiopulmonary bypass did not significantly impact cancer specific survival or overall survival in patients undergoing nephrectomy and level III or IV tumor thrombectomy. Neither approach was independently associated with increased mortality on multivariate analysis. Greater surgical complications were not independently associated with the use of cardiopulmonary bypass.

Purpose: The aim of this study was to evaluate the utility of the DNA integrity assay (DIA) as a plasma-based screening tool for the detection of prostate cancer. Experimental Design: Blood samples were collected from patients with biopsy-proven prostate cancer prior to prostatectomy (n = 123) and processed as two-spin plasma preparations. The three control groups included: males Results: Patients with prostate cancer (86 of 123; 69.9%) were determined to have a positive DIA score of ≥7. The DIA results from control groups 1, 2, and 3 showed specificities of 90%, 92%, and 68.2%, respectively. Of the patients with negative age-adjusted prostate-specific antigen (PSA) and prostate cancer, 19 of 30 (63%) had a positive DIA score. The area under the receiver operating characteristic curve for DIA was 0.788. Conclusion: While detecting 69.9% of those with prostate cancer, DIA maintained an overall specificity of 68.2% to 92%, a range favorably comparable to that currently accepted for PSA (60-70%). The variability in specificity between control groups is likely explained by the established 19% to 30% detection of prostate cancer on subsequent biopsies associated with control group 3. DIA detected 63% of the prostate cancers undetected by currently accepted PSA ranges.

The topics covered in this section include renal, prostate, bladder and testicular cancer. As can be seen, these contributions come from all over the world and are of interest for several reasons. For example, the first paper, from the USA, describes the management of RCC with vena caval and atrial extension, using minimal access as against median sternotomy with circulatory arrest. Other more unusual subjects include RCC of native kidneys in renal-transplant recipients and radical prostatectomy in patients with HIV. OBJECTIVE To review our experience with approaches for managing renal cell carcinoma (RCC) with venous thrombi extension at and above the level of the hepatic veins, comparing surgery and peri-operative outcomes in patients with cardiopulmonary bypass (CPB) with deep hypothermic cardiac arrest (DHCA) either by minimal access (MA) or traditional median sternotomy (TMS). PATIENTS AND METHODS From 1986 to 2005, 50 radical nephrectomies with inferior vena cava (IVC) thrombectomies were performed at our institution using TMS (22 patients) and MA (28) techniques. Patient demographics were compared using Student’s t-, Fisher’s exact and Pearson chi-square tests. The duration of surgery, CPB, DHCA, mechanical ventilation, length of stay, and peri-operative transfusion requirements, were compared using the Mann–Whitney U-test. Estimates of survival were constructed using Kaplan–Meier curves and analysed with the log-rank test. Subgroups were analysed excluding TMS patients undergoing concurrent coronary revascularization. RESULTS There were no significant differences in patient demographics or comorbidities between the MA and TMS group. There were significant decreases in the MA vs the TMS group (P

Ileal and intestinal ureteral replacement remains a useful procedure for complex ureteral reconstruction. We examined the long-term safety and efficacy of this procedure, especially in regard to maintaining preoperative renal function and the avoidance of major complications.A total of 56 patients underwent intestinal ureteral substitution at our institution between 1979 and 2003, including 52 with an ileal ureteral replacement, 2 with colonic replacement alone and 2 with bilateral ureteral replacement, necessitating ileum and colon for 1 ureter each. The factors reviewed were indications for surgery, type of ureteral replacement, and the presence and type of complications. Followup data included excretory urogram or equivalent imaging results, and measurement of serum chloride, bicarbonate and creatinine before and after the procedure.Overall the complication rate remained low. Mean followup was 6.04 years (median 3.2). Most postoperative complications, which occurred in 10 patients (17.9%), were minor in nature, including pyelonephritis, fever of unknown origin, neuroma, hernia, recurrent urolithiasis and deep venous thrombosis. Major complications occurred in 6 patients (10.5%), including anastomotic stricture, ileal graft obstruction, wound dehiscence and chronic renal failure. Overall patients did not experience worsening renal function after the procedure with equivalent median creatinine before and after the procedure (1.0 mg/dl).During long-term followup major complications are rare and renal function remains preserved. Ileal and intestinal ureteral substitution remains a safe and efficacious procedure in patients with complex and difficult ureteral issues not amenable to more conservative measures.

OBJECTIVE To evaluate PP2 as a modulator of the cadherin/catenin complex in late-stage bladder carcinoma cells, and to assess its potential invasion-suppressor activity in this model. MATERIALS AND METHODS A panel of five human bladder carcinoma cells, characterizing late-stage disease, was used to determine the concentration for 50% inhibition of PP2 in cell-proliferation assays. Modulation of cadherin/catenin expression by PP2 was determined in Western blot analysis, with an assessment of the activation status of mitogen-activated protein kinase and Akt signalling pathways. Altered invasive capacity linked to these variables was determined in standard in vitro invasion assays. RESULTS PP2 elicited concentration-dependent growth inhibition in all bladder cell lines within the panel, with growth suppression recorded at 10–35 µmol/L PP2. Distinct morphological changes were recorded in cell lines exposed to PP2, accompanied by up-regulation of plakoglobin expression in a subset of lines. Exposure of cells to PP2 resulted in inactivation of Akt in all cells and a concomitant reduction in in vitro invasive capacity. CONCLUSIONS These results show that PP2 inhibits bladder carcinoma cell growth and can modulate plakoglobin expression in a subset of cell lines. In addition, PP2 can suppress the in vitro invasive capacity of bladder carcinoma cells by modulating the activation status of Akt.

The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with

To compare the morbidity, mortality and clinical outcome of catheterizable continent urinary reservoirs (CUR) with orthotopic neobladders (ONB) at our institution.Between September 1985 and October 2001, 238 patients (84 women and 154 men) had a continent urinary diversion, including 125 ONBs and 113 CURs. The charts of these patients were reviewed retrospectively and the patients interviewed by telephone when possible (for continence data and overall satisfaction). Over the 16 years the relative frequency of ONB diversion increased steadily and thus the mean follow-up was significantly longer for the CUR (9.4 years) than for the ONB group (5.2 years) (P0.001). This bias was addressed by comparing these large groups for the early outcome only. Separately, the long-term outcome was analysed, comparing the 40 most recently constructed CURs with all 113 ONBs; this gave a mean follow-up of 5.2 years for ONB and 5.9 years for CUR (not significant, P = 0.23).Of the 238 continent diversions, 125 were ONBs and 113 CURs; most patients had a diagnosis of transitional cell carcinoma before surgery. The mean age at surgery was 59.1 years for the ONB and 54.8 years for the CUR group (P0.001). Men were significantly more likely than women to have had an ONB. There were two deaths after surgery in the ONB and none in the CUR group. The hospital stay was significantly longer for the CUR than for the ONB group; the likelihood of an intensive care unit stay, estimated blood loss and reoperation rate were higher in the CUR group. There was no significant difference in the rates of short-term (30 days) complications. The analysis of the time-controlled groups showed significantly more long-term (30 days) complications and of reoperation in the CUR group. Fifty-one patients with ONB and 19 with CURs were contacted by telephone; of those with an ONB, 43 (84%) had daytime continence (1 pad/day) while 13 (25%) were continent at night (1 pad). Fifteen of 19 with a CUR reported full day and night-time continence. From separate telephone interviews, overall satisfaction was high for both groups (mean 4.5, scale 0-5), expectations were met in 92% for both, and 94% in both would choose the same procedure again if confronted with the same set of circumstances.Both ONB and CUR offer an excellent functional outcome, as reflected by patient satisfaction and continence rates.

Histone deacetylase inhibitors (HDACis) are emerging as a promising new class of anticancer agents displaying growth-inhibitory activity and low toxicity in vivo. In this study, we examined the effect of sodium butyrate (NaB) and trichostatin A (TSA) on the growth of human bladder carcinoma cell lines in culture and TSA on the growth of EJ and UM-UC-3 human bladder xenografts in nude mice. NaB and TSA suppressed the growth of bladder cell lines at millimolar (1.5-4.3 mM) and micromolar (0.03-0.33 microM) concentrations, respectively, inducing concentration-dependent cell death. Bladder carcinoma cells within the experimental panel displayed the phenotype of late-stage bladder lesions expressing N-cadherin in the absence of E-cadherin accompanied by low levels of plakoglobin expression. Exposure of these cells to HDACis resulted in upregulation of plakoglobin with no change in E-cadherin expression. A 2-hr exposure to TSA was the minimal time required to upregulate plakoglobin in cells with downregulation to baseline levels occurring within 24 hr following drug removal. In mice bearing EJ and UM-UC-3 bladder xenografts, TSA (500 microg/kg/day) caused suppression of tumor growth compared with mice receiving vehicle alone. A > 70% reduction in mean final tumor volume was recorded in both bladder xenograft models with no detectable toxicity. The results suggest that TSA inhibits bladder carcinoma cell growth and may be a useful, relatively nontoxic agent for consideration in the treatment of late-stage bladder tumors.