Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma.

OBJECTIVE: To identify microRNA (miRNA) characteristic of metastatic clear cell renal cell carcinoma (ccRCC) and those indicative of cancer-specific survival (CSS) 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 and n = 46, respectively). Samples were grouped: benign, non-progressive, and progressive ccRCC. MiRNAs were profiled by microarray and validated by quantitative reverse transcription-polymerase chain reaction. Biomarker signatures were developed to predict cancer status in nephrectomy and biopsy specimens. CSS was examined using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Microarray analysis revealed 20 differentially expressed miRNAs comparing non-progressive with progressive tumours. A biomarker signature validated in nephrectomy specimens had a sensitivity of 86.7% and a specificity of 92.9% for differentiating benign and ccRCC specimens. A second signature differentiated non-progressive vs 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 CSS. CONCLUSION: This study identified miRNAs differentially expressed in ccRCC samples; as well as those correlating with CSS. 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.

Renal cell carcinoma with inferior vena cava involvement: Prognostic effect of tumor thrombus consistency on cancer specific survival.

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.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cardiopulmonary Bypass has No Significant Impact on Survival in Patients Undergoing Nephrectomy and Level III-IV Inferior Vena Cava Thrombectomy: Multi-Institutional Analysis.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lessons learned from the International Renal Cell Carcinoma-Venous Thrombus Consortium (IRCC-VTC).

Renal cell carcinoma (RCC) extension into the renal vein or the inferior vena cava occurs in 4%-10% of all kidney cancer cases. This entity shows a wide range of different clinical and surgical scenarios, making natural history and oncological outcomes variable and poorly characterized. Infrequency and variability make it necessary to share the experience from different institutions to properly analyze surgical outcomes in this setting. The International Renal Cell Carcinoma-Venous Tumor Thrombus Consortium was created to answer the questions generated by competing results from different retrospective studies in RCC with venous extension on current controversial topics. The aim of this article is to summarize the experience gained from the analysis of the world's largest cohort of patients in this unique setting to date.

Temporary targeted renal blood flow interruption using a reverse thermosensitive polymer to facilitate bloodless partial nephrectomy: a swine survival study.

UNLABELLED: What's known on the subject? and What does the study add? Lumagel™ 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, Lumagel™ 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 Lumagel™ 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), Lumagel™ (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.

Non-clamped partial nephrectomy: techniques and surgical outcomes.

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.

Comparison of hilar clamping and non-hilar clamping partial nephrectomy for tumours involving a solitary 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.

Novel ZEB1 expression in bladder tumorigenesis.

UNLABELLED: 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.

Identification of tumor and invasion suppressor gene modulators in bladder cancer by different classes of histone deacetylase inhibitors using reverse phase protein arrays.

PURPOSE: We assessed the ability of different classes of histone deacetylase inhibitors to target tumor and invasive suppressor genes in a panel of bladder carcinoma cell lines using reverse phase protein arrays. MATERIALS AND METHODS: Three poorly, moderately and highly invasive cell lines were exposed to histone deacetylase inhibitors, trichostatin A, apicidin, valproic acid (Sigma) and MS-275 (AXXORA) for 0 to 36 hours. Lysates were harvested and arrayed in a 10-fold dilution series in duplicate. Data points were collected and analyzed using a concentration interpolation methodology after normalization. RESULTS: Protein expression profiles revealed up-regulation of gamma-catenin in highly invasive lines, and alpha-catenin in moderately and highly invasive lines after exposure to all histone deacetylase inhibitors, apicidin and MS-275, respectively. Gelsolin was up-regulated in poorly and moderately invasive lines after exposure to all histone deacetylase inhibitors. Desmoglein was down-regulated in poorly and moderately invasive cell lines by all 4 histone deacetylase inhibitors, in addition to decreased FAK (Transduction Laboratories) expression in moderately and highly invasive lines exposed to valproic acid and MS-275. CONCLUSIONS: Different histone deacetylase inhibitor classes have the potential to modulate tumor and invasive suppressor gene expression, identifying histone deacetylase inhibitors as potential therapeutic agents for bladder cancer. Reverse phase protein arrays enable high throughput screening of multiple compounds to assess the expression profile of specific protein groups targeted for therapy.

Endovascular temporary vessel occlusion with a reverse-thermosensitive polymer for bloodless minimally invasive renal surgery.

PURPOSE: To demonstrate the feasibility of reversible vessel embolization with angiographic guidance for delivery of a rapid reverse-thermosensitive polymer to provide hemostasis as an aid for minimally invasive renal surgery in a porcine model. MATERIALS AND METHODS: After isolation of the left kidney of seven anesthetized pigs (50-70 kg) with a surgical robot, a renal angiogram of both kidneys was obtained. A 5-F angiographic catheter was used to selectively embolize a lower-pole segmental artery of the right and left kidney with a thermosensitive polymer (LeGoo-XL). Distal and proximal embolization of the target vessel was compared. Degree and duration of hemostasis and reversibility was determined. After complete hemostasis was obtained angiographically, a partial robotic lower-pole nephrectomy was performed on the left kidney only. RESULTS: Only proximal embolization provided controllable hemostasis. A 20% polymer concentration in a buffer solution of 40% saline solution and 40% iodine contrast medium by weight injected at room temperature resulted in a reproducible embolus for more than 30 minutes, the time needed to perform a partial nephrectomy. The radiographic appearance of the embolus was used to determine the total amount of polymer needed. Cold saline solution completely dissolved any residual polymer at the end of surgery. CONCLUSIONS: Proximal arterial occlusion with a thermosensitive polymer can be rapidly reversed with selective intraarterial infusion of chilled saline solution. Preceding nephron-sparing surgery with transcatheter embolization of the relevant branch of the renal artery with the polymer can facilitate the procedure and ought to be investigated further.

Temporary segmental renal artery occlusion using reverse phase polymer for bloodless robotic partial nephrectomy.

PURPOSE: Renal vascular clamping with ensuing warm ischemia is typically needed during robotic or laparoscopic partial nephrectomy. We developed a technique for angiographic delivery of the novel intra-arterial reverse thermoplastic polymer LeGoo-XL that allows temporary selective vascular occlusion with normal perfusion of the remaining kidney. MATERIALS AND METHODS: Eight pigs underwent a total of 16 selective angiographic occlusions of the lower pole segmental artery using gel polymer. The technical feasibility of 2 hemostatic techniques, perfusion hemostasis and local plug formation, was assessed in 4 pigs each. Selective ischemia time was recorded and the vascular occlusion site was noted radiographically and laparoscopically. The feasibility of reversing the polymer from solid back to liquid state to allow reperfusion was determined. Pathological analysis of the kidney was completed in these acute model pigs. In the last 2 cases lower pole robotic partial nephrectomy was done using the da Vinci surgical system. RESULTS: Selective lower pole ischemia was achieved in all 8 cases. Perfusion hemostasis yielded an inconsistent duration of occlusion (zero to greater than 60 minutes). Vascular occlusion time using local plug formation was more reliable (17 to 30 minutes) with consistent ability to reverse the plug to liquid state by cold saline flush. Two lower pole robotic partial nephrectomies were completed with minimal blood loss. CONCLUSIONS: We developed a reliable technique of angiographic delivery of gel polymer for temporary vascular occlusion of selective renal artery branches using local plug formation. Ongoing studies are under way to assess technique consistency and the long-term effects of the polymer.

A novel approach to using matrix metalloproteinases for bladder cancer.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of an organ transplant-based approach with a dramatic reduction in postoperative complications following radical nephrectomy and tumor thrombectomy in renal cell carcinoma.

OBJECTIVES: Our aim was to determine whether using an organ transplant-based(TB) approach reduces postoperative complications(PCs) following radical nephrectomy(RN) and tumor thrombectomy(TT) in renal cell carcinoma(RCC) patients with level II-IV thrombi. METHODS: A total of 390(292 non-TB/98 TB) IRCC-VT Consortium patients who received no preoperative embolization/IVC filter were included. Stepwise linear/logistic regression analyses were performed to determine significant multivariable predictors of intraoperative estimated blood loss(IEBL), number blood transfusions received, and overall/major PC development within 30days following surgery. Propensity to receive the TB approach was controlled. RESULTS: The TB approach was clearly superior in limiting IEBL, blood transfusions, and PC development, even after controlling for other significant prognosticators/propensity score(P < .000001 in each case). Median IEBL for non-TB/TB approaches was 1000 cc/300 cc and 1500 cc/500 cc for tumor thrombus Level II-III patients, respectively, with no notable differences for Level IV patients(2000 cc each). In comparing PC outcomes between non-TB/TB patients with a non-Right-Atrium Cranial Limit, the observed percentage developing a: i) PC was 65.8%(133/202) vs. 4.3%(3/69) for ECOG Performance Status(ECOG-PS) 0-1, and 84.8%(28/33) vs. 25.0%(4/16) for ECOG-PS 2-4, and ii) major PC was 16.8%(34/202) vs. 1.4%(1/69) for ECOG-PS 0-1, and 27.3%(9/33) vs. 12.5%(2/16) for ECOG-PS 2-4. Major study limitation was the fact that all TB patients were treated by a single, experienced, high volume surgeon from one center (non-TB patients were treated by various surgeons at 13 other centers). CONCLUSIONS: Despite this major study limitation, the observed dramatic differences in PC outcomes suggest that the TB approach offers a major breakthrough in limiting operative morbidity in RCC patients receiving RN and TT.

P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells.

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: The absence of P-cadherin staining was associated with muscle-invasive disease, grade 3 (P < 0.001) and nodal disease (P = 0.009). Similar results were obtained when considering cytoplasmic and unrestricted localization of P-cadherin (P < 0.001), 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%). CONCLUSIONS: 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.

Prognostic significance of altered p120 ctn expression in bladder cancer.

OBJECTIVE: To identify the frequency of change in the expression and localization of p120(ctn) in bladder tumours and its association with clinical outcomes, and to investigate the potential role of p120(ctn) in the migratory and invasive behaviour of bladder carcinoma cells. MATERIALS AND METHODS: In all, 425 superficial tumour specimens (Ta, Tis and T1) and 305 invasive (T2-T4) tumour specimens from 534 patients were assembled in 10 tissue microarrays. P120(ctn) immunostaining was scored for intensity and cellular localization and correlated with clinical variables and survival analysis. Knockdown of p120(ctn) was achieved using small-interference RNA (siRNA) followed by the assessment of migration and invasion behaviour in standard in vitro assays. RESULTS: The expression levels of p120 catenin inversely correlated with pathological tumour stage (P < 0.001), histological grade (P < 0.001), presence of lymphovascular invasion (P = 0.02) but not lymph node (LN) involvement (P = 0.17). Non-membranous localization of p120(ctn) correlated with stage (P < 0.001), grade (P < 0.001), lymphovascular invasion (P = 0.04) and LN-positive disease (P = 0.02). A low expression level of p120(ctn) was linked to a poor outcome in cancer-specific survival analysis. Knockdown of p120(ctn) using siRNA resulted in a significant reduction in the migration and invasive potential of bladder carcinoma cells. CONCLUSIONS: Our findings suggest that p120(ctn) acts as a prognostic factor in bladder tumours and has a primary role to play in the migratory and invasive behaviour of bladder carcinoma cells.

Resection of renal tumors invading the vena cava.

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.

Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors.

PURPOSE: Epithelial to mesenchymal transition (EMT) is reportedly an important transition in cancer progression in which the underlying cellular changes have been identified mainly using in vitro models. In this study, we examined the expression pattern of EMT markers in vivo and determined the occurrence and clinical significance of these events in a series of bladder carcinomas. EXPERIMENTAL DESIGN: Eight hundred and twenty-five tumor samples from 572 bladder cancer patients were assembled in 10 tissue microarrays. Paraffin sections from each tissue microarray were subjected to antigen retrieval and processed by immunohistochemistry for the expression of E-cadherin, plakoglobin, beta-catenin, N-cadherin, and vimentin. RESULTS: Pathologic expression of E-cadherin, beta-catenin, plakoglobin, and vimentin were associated with the clinicopathologic variables of grade and stage with only the cytoplasmic localization of plakoglobin found associated with lymph node status. Associations between the aforementioned markers were found significant as determined by the Spearman correlation coefficient with N-cadherin showing no associations in this analysis. In univariate survival analysis involving patients who underwent cystectomy, the reduction or loss of plakoglobin significantly influenced overall survival (P = 0.02) in which the median time to death was 2 years compared with 4 years when a normal level of plakoglobin was recorded. When the analysis was done for cancer-specific survival, low levels of both plakoglobin (P = 0.02) and beta-catenin (P = 0.02) significantly influenced survival. CONCLUSION: The putative markers of EMT defined within a panel of bladder carcinoma cell lines were recorded in vivo, frequently associated with tumors of high grade and stage. Although multivariate analysis showed no significant influence of the EMT biomarkers on survival, alterations associated with plakoglobin were identified as significant prognostic features in these tumors.

Surgical management of large renal tumors.

In addition to an increased occurrence of small, localized, incidentally discovered renal cell carcinomas (RCCs), there has been an upward trend in the incidence of advanced renal tumors per unit of population and in disease mortality worldwide. As radical nephrectomy remains the standard of care in treating localized RCC, this manuscript focuses on surgical approaches. We defined 'large renal tumors' as those greater than 7 cm or those with venous involvement. We discuss operative strategies in both open and laparoscopic surgery as well as approaches to special circumstances, including patients with tumor thrombus and the indications for nephron-sparing surgery in patients with greater than T2 RCC. The literature pertaining to controversial areas such as preoperative renal artery embolization and the clinical utility of metastectomy and cytoreductive therapy are also reviewed. The theoretical basis and potential applications of neoadjuvant therapy for larger renal tumors is examined as well.

Is imperative partial nephrectomy feasible for kidney cancer with venous thrombus involvement? Outcomes of 42 cases and matched pair analysis with a large radical nephrectomy cohort.

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 ± 27.0ml/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 ± 0.6mg/dl and -23.2 ± 37.3ml/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.