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UGN-101 (mitomycin for pyelocalyceal solution) is a recently approved chemoablative treatment for low-grade (LG) upper tract urothelial carcinoma (UTUC). While approved for retrograde or antegrade administration, previous reports discuss only patients treated by retrograde approach. We report our techniques for antegrade administration along with early outcomes from our cohort of patients who have undergone UGN-101 administration via nephrostomy.UGN-101 is administered as 6 weekly instillations in patients who have undergone endoscopic ablation of LG UTUC. We outline our approach in patients thought to have LG UTUC from initial ureteroscopy to nephrostomy placement, UGN-101 administration and eventual nephrostomy removal. We discuss early durability of response along with adverse events with special attention to ureteral strictures.Eight patients underwent antegrade UGN-101 administration during the study period, all of whom underwent followup ureteroscopy with complete response in 4 patients. Three patients reported 5 adverse events-3 grade 1, 1 grade 2 requiring 1 week delay of treatment and 1 asymptomatic ureteral stricture. Median followup was 7 months.We outline our approach for antegrade administration of UGN-101 and discuss early results along with adverse events. Future studies should evaluate our method's potential to increase patient comfort, improve logistics and decrease risk of adverse events.

The incidence and risk factors for metachronous upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) remain incompletely defined, which has limited the ability to individualize postoperative surveillance.A retrospective review of 2 institutional registries was performed to identify patients undergoing RC for urothelial carcinoma. Multivariable Cox proportional hazard models for metachronous post-RC UTUC were developed in one institutional data set and validated in the second institutional data set. A post-RC UTUC risk score was then developed from these models.A total of 3,170 RC patients were included from the training cohort and 959 RC patients from the validation cohort. At a median followup after RC of 4.6 years (IQR 2.1-8.7), 167 patients were diagnosed with UTUC. On multivariable analysis in the training cohort, risk factors for metachronous UTUC were the presence of positive urothelial margin (HR 2.60, p0.01), history of bacillus Calmette-Guérin treatment prior to RC (HR 2.20, p0.01), carcinoma in situ at RC (HR 2.01, p0.01) and pre-RC hydronephrosis (HR 1.48, p=0.04). These factors had similar discriminative capacity in the training and validation cohorts (C-statistic 0.71 and 0.73, respectively). A UTUC risk score was developed with these variables which stratified patients into low (0 points), intermediate (1-3 points), and high risk (4+ points) for post-RC UTUC, with respective 5-year UTUC-free survivals of 99%, 96%, 89% in the training cohort and 98%, 96%, and 91% in the validation cohort.We developed and validated a risk score for post-RC UTUC that may optimize UTUC surveillance protocols after RC.

Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort.We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence.A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031).IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

We report the reliability of computerized tomography urography and ureteroscopy in the diagnosis and management of upper tract urothelial carcinoma.From 2015 to November 2018 we prospectively collected and retrospectively analyzed 244 cases of ureteroscopy with available preoperative computerized tomography urography. Computerized tomography urography was categorized as positive, suspicious, unlikely and negative. Correspondence between imaging, ureteroscopy and histology was analyzed. The therapeutic indication, based on 2020 EAU Guidelines and patient clinical data, was recorded before and after ureteroscopy. Cohen's Kappa was used for agreement analysis. Logistic regression was used for prediction of positive ureteroscopy.Ureteroscopy was positive for upper tract urothelial carcinoma in 107/115 (93%), 48/77 (62.3%), 15/27 (55.6%) and 12/25 (48%) cases with positive, suspicious, unlikely and negative computerized tomography urography, respectively. On cytohistology the result was confirmed in 164/182 (90.1%) cases. The positive predictive value of a filling defect, stenosis, thickening and hydronephrosis on computerized tomography urography was 87.7% (121/138 cases), 65.6% (21/32), 69.6% (64/92) and 79.7% (59/74), respectively. On multivariate analysis a filling defect (95% CI 2.76-11.5, OR 5.63, p0.0001) or hydronephrosis (1.04-6.18, OR 2.52, p=0.04) was associated with ureteroscopy outcome. Among cases with positive computerized tomography urography and ureteroscopy, the lesions differed in dimensions (20/107), number (14/107) and site (11/107), for a total of 45/107 (42.1%) cases. The indication of elective treatment changed after ureteroscopy in 37/76 (48.1%) cases (Kappa=0.31), as 17/28 (60.7%), 11/20 (55%) and 11/28 (39.2%) indications were confirmed for endoscopic management, ureterectomy and nephroureterectomy, respectively.The complementary use of computerized tomography urography and ureteroscopy in the diagnostic workup of upper tract urothelial carcinoma should be evaluated.

Upper tract urothelial carcinoma with clinically positive regional lymph nodes is an aggressive disease state with a high propensity for metastasis and death. The current literature is limited regarding national practice patterns and outcomes in this patient population.We identified 1,658 patients in the NCDB (National Cancer Database) who had cN+M0 upper tract urothelial carcinoma. Patients were stratified into treatment groups. We compared baseline patient and tumor characteristics between the groups, and completed survival analysis using a multivariate Cox regression model.There were 1,658 patients in the final study population. Preoperative chemotherapy was the least performed treatment. That group comprised 6.8% of the overall population and was associated with the highest median overall survival of 36 months compared to 21 months for adjuvant chemotherapy, 14 for chemotherapy only, 10 for surgery without perioperative chemotherapy and 5 for no treatment. On multivariate analysis preoperative chemotherapy was associated with improved median overall survival compared to that in the adjuvant chemotherapy group (HR 0.58, 95% CI 0.38-0.87). There was no statistically significant difference in survival between the chemotherapy only and the surgery only groups. Of patients in the preoperative chemotherapy group 34.6% achieved pN0 status compared to 10.3% of those who underwent surgery as initial therapy.Preoperative chemotherapy was the least performed treatment strategy in the management of cN+M0 upper tract urothelial carcinoma but it was associated with the highest median overall survival. There was no difference in survival between the chemotherapy only and the surgery only groups. Overall these results suggest that initial chemotherapy is appropriate in this population when feasible.

We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors.We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade.At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant.Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

We investigated the prognostic value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma.Tissue microarrays of 423 patients treated with extirpative surgery for high grade upper tract urothelial carcinoma from the International Upper Tract Urothelial Carcinoma collaboration were stained for PD-1 and PD-L1 using antibodies, including Cell Marque™ NAT105 diluted 1:250 and prediluted E1L3N® via immunohistochemistry. A 1% or greater staining rate of tumor infiltrating lymphocytes (PD-1) and tumor cells (PD-L1) was considered positive. Univariate and multivariate analyses were performed to assess independent prognosticators of survival outcomes.Median patient age was 70.0 years and median followup was 37.0 months. PD-1 and PD-L1 were positive in 37.2% and 26.2% of patients, respectively. PD-1 positivity was significantly associated with adverse pathological characteristics while PD-L1 positivity was associated with favorable pT stage. On univariate analysis PD-1 expression was associated with worse recurrence-free, cancer specific and overall survival. On multivariate analysis PD-1 expression was an independent prognosticator of cancer specific survival (HR 1.7, 95% CI 1.03-2.66, p = 0.039) and overall survival (HR 1.5, 95% CI 1.05-2.24, p = 0.029) but not recurrence-free survival (HR 1.4, 95% CI 0.9-2.16, p = 0.139). On univariate analysis PD-L1 expression was not significantly associated with survival outcomes. However, on multivariate analysis in patients with organ confined disease (pT2 or less, pN0/x and cM0), PD-L1 positivity was an independent prognosticator of recurrence-free survival (HR 0.2, 95% CI 0.06-0.98, p = 0.046) and overall survival (HR 0.3, 95% CI 0.11-0.63, p = 0.003).PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and independent prognostication of worse survival outcomes. PD-L1 positivity of tumor cells was an independent prognosticator of favorable survival outcomes in cases of organ confined disease.

Since conditional survival analysis provides better estimates of survival time at each followup, we assessed changes in conditional intravesical recurrence-free survival rates after radical nephroureterectomy. We also sought to determine how the impact of well-known risk factors evolves with time, particularly in patients with localized upper tract urothelial carcinoma.We identified 364 patients with Ta-3N0M0 localized upper tract urothelial carcinoma who underwent open or laparoscopic radical nephroureterectomy at 1 of our 3 institutions. Conditional intravesical recurrence-free and cancer specific survival rates were calculated using the Kaplan-Meier method. The changing impact of parameters on intravesical recurrence with time was assessed by multivariate Cox regression analysis.Intravesical recurrence after radical nephroureterectomy was detected in 176 patients (48.4%) and 93 (25.5%) died of localized upper tract urothelial carcinoma. Five-year intravesical recurrence-free and cancer specific survival rates after surgery were 41.5% and 72.9%, respectively. Based on 1, 2, 3 and 4-year survivorship the 5-year conditional intravesical recurrence-free survival rate increased from 41.5% to 60.5%, 73.4%, 79.5% and 96.7%, respectively. The 5-year conditional cancer specific survival rate also improved from 72.9% to 78.4%, 85.4%, 90.9% and 95.5% at 1, 2, 3 and 4 years, respectively. The effects of well-known predictive factors on estimated conditional survival decreased with time for intravesical recurrence. In contrast, the impact of T2 or lower pathological stage and laparoscopic radical nephroureterectomy sustained statistical power with time.Conditional survival analysis revealed that the probability of intravesical recurrence-free survival increased with time in patients with localized Ta-3N0M0 upper tract urothelial carcinoma after radical nephroureterectomy. Patients with T2 or lower T stage who undergo laparoscopic radical nephroureterectomy may be recommended for longer followup to detect subsequent intravesical recurrence.

Patients with bladder cancer who present with hydronephrosis may require drainage of the affected kidney before receiving further cancer treatment. Drainage can be done by retrograde stenting or percutaneously. However, retrograde stenting carries the risk of tumor cell spillage to the upper urinary tract. The aim of this study was to evaluate whether patients with bladder cancer are at higher risk for upper urinary tract recurrence if retrograde stenting has been performed prior to radical cystectomy.We retrospectively analyzed the records of 1,005 consecutive patients with bladder cancer who underwent radical cystectomy at our department between January 2000 and June 2016. Negative intraoperative ureteral margins were mandatory for study inclusion. Patients received regular followup according to our institutional protocol, including imaging of the upper urinary tract and urine cytology.Preoperative drainage of the upper urinary tract was performed in 114 of the 1,005 patients (11%), including in 53 (46%) by Double-J® stenting and in 61 (54%) by percutaneous nephrostomy. Recurrence developed in the upper urinary tract in 31 patients (3%) at a median of 17 months after cystectomy, including 7 of 53 (13%) in the Double-J group, 0% in the nephrostomy group and 24 of 891 (3%) in the no drainage group. Multivariate regression analysis revealed a higher risk of upper urinary tract recurrence if patients underwent Double-J stenting (HR 4.54, 95% CI 1.43-14.38, p = 0.01) and preoperative intravesical instillations (HR 2.94, 95% CI 1.40-6.16, p = 0.004).Patients who undergo Double-J stenting prior to radical cystectomy are at higher risk for upper urinary tract recurrence. If preoperative upper urinary tract drainage is required, percutaneous drainage might be recommended.

We evaluated differences in clinicopathological characteristics and oncologic outcomes between patients with upper tract urothelial carcinoma in mainland China and the United States.We retrospectively compiled clinicopathological and oncologic outcomes data on patients with upper tract urothelial carcinoma treated surgically at tertiary care medical facilities in the United States or China from 1998 to 2015. Baseline demographics, comorbidities and pathological features were evaluated. Oncologic end points, including intravesical recurrence and cancer specific survival, were obtained after excluding patients who received systemic chemotherapy. Multivariable Cox regression was performed to determine predictors of adverse oncologic outcomes for each country.A total of 775 patients with upper tract urothelial carcinoma were identified, including 451 in China and 324 in the United States. Median followup was 42 months. American patients were more frequently male (65% vs 44%) and smokers (79% vs 18%), and had a worse mean ASA® (American Society of Anesthesiologists®) score (2.7 vs 2.2) and prior bladder cancer (41% vs 4%, all p 0.001). Chinese patients more often had preoperative hydronephrosis (56% vs 40%), high grade pathology (98% vs 77%), muscle invasion (64% vs 38%) and nodal metastases (26% vs 6%, all p0.001). American patients had worse overall survival on Kaplan-Meier analysis (p = 0.049). However, country of origin did not predict local relapse or cancer specific survival.Patient and disease characteristics of upper tract urothelial carcinoma differed between the Chinese and American cohorts. Chinese patients appeared relatively healthier at presentation but more often exhibited adverse pathological features. While evaluation and management patterns may account for these variations, the pathological findings may reflect a differential underlying pathogenesis of disease. Additional study is warranted to further characterize these differences.

Increasing evidence has shown that protein tyrosine phosphatases have dominant roles in setting the levels of tyrosine phosphorylation and promoting oncogenic processes. PTP4A3 has been implicated in cancer metastasis but to our knowledge the role of PTP4A3 in upper tract urothelial carcinoma is unknown. The aim of this study was to investigate the association of PTP4A3 with disease characteristics, distant metastasis and prognosis of upper tract urothelial carcinoma.The importance of PTP4A3 was initially examined in paired normal urothelium, noninvasive upper tract urothelial carcinoma, invasive upper tract urothelial carcinoma and nodal metastatic tissue. The PTP4A3 transcript level was assessed in another 20 upper tract urothelial carcinoma samples by real-time reverse transcriptase-polymerase chain reaction. PTP4A3 protein expression was determined by immunohistochemistry using the H-score in 340 upper tract urothelial carcinoma samples. It was further correlated with clinicopathological factors, and disease specific and metastasis-free survival.The expression of PTP4A3 significantly increased from normal urothelium, noninvasive upper tract urothelial carcinoma and invasive upper tract urothelial carcinoma to nodal metastatic tissue (p0.001). The PTP4A3 transcript level was also markedly up-regulated in higher stage upper tract urothelial carcinoma (p = 0.002). Over expression of PTP4A3 protein was significantly associated with advanced pT status, nodal metastasis, lymphovascular invasion and perineural invasion (each p0.001) as well as with inferior disease specific and metastasis-free survival on multivariate analysis (each p 0.0001). In addition, it predicted metastasis in patients with pTa, pT1 and pT2 upper tract urothelial carcinoma.Results imply that PTP4A3 has a role in the carcinogenesis of upper tract urothelial carcinoma. PTP4A3 over expression independently predicted the metastasis and outcome of upper tract urothelial carcinoma, which was even more important in organ confined disease.

We validate the independent predictive value of Ki-67 in patients with high grade upper tract urothelial carcinoma.A total of 475 patients from the international Upper Tract Urothelial Carcinoma Collaboration who underwent extirpative surgery for high grade upper tract urothelial carcinoma were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray formed from this patient cohort. Ki-67 expression was assessed in a semiquantitative fashion and considered over expressed at a cutoff of 20%. Multivariate analyses were performed to assess independent predictors of oncologic outcomes and Harrell's C indices were calculated for predictive models.The median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was over expressed in 25.9% of patients. Ki-67 over expression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ and regional lymph node metastases. On Kaplan-Meier analyses over expressed Ki-67 was associated with worse recurrence-free survival (HR 12.6, p0.001) and cancer specific survival (HR 15.8, p0.001). On multivariate analysis Ki-67 was an independent predictor of recurrence-free survival (HR 1.6, 95% CI 1.07-2.30, p=0.021) and cancer specific survival (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved Harrell's C index from 0.66 to 0.70 (p0.0001) for recurrence-free survival as well as cancer specific survival in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for recurrence-free survival and 0.81 to 0.83 (p=0.005) for cancer specific survival in our postoperative model.Ki-67 was validated as an independent predictor of recurrence-free survival and cancer specific survival in patients treated with extirpative surgery for high grade upper tract urothelial carcinoma in a large, multi-institutional cohort.

Recent studies have suggested that lymph node dissection may improve the prognosis in patients with upper tract urothelial carcinoma. Therefore, patients who will benefit from lymph node dissection need to be selected before surgery. Because patients who have extraurothelial recurrence theoretically include those whose prognoses are improved by lymph node dissection, we conducted this study to determine the preoperative predictors of extraurothelial recurrence in patients with ureteral cancer.Because it is not appropriate to categorize the preoperative radiologic findings of ureteral cancer and those of renal pelvic cancer using the same classification criteria, we focused on ureteral cancer. We reviewed preoperative factors in 70 patients with ureteral cancer treated with radical nephroureterectomy. Laboratory tests including inflammatory indices, tumor markers and estimated glomerular filtration rate, along with radiologic findings, were evaluated. Multivariate analyses were performed to determine independent factors predicting extraurothelial recurrence in patients with ureteral cancer.Positive cytology, cT stage 3 or greater, length of ureteral cancer 3 cm or greater and estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 were independent predictors of extraurothelial recurrence on multivariate analysis. When patients were stratified into 3 groups according to the number of risk factors, the 3-year extraurothelial recurrence-free survival rates were 95.2% in the low risk group, 75.8% in the intermediate risk group and 25.1% in the high risk group.Positive cytology, cT stage 3 or greater, length of ureteral cancer 3 cm or greater and estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 were preoperative predictive factors of extraurothelial recurrence in patients with ureteral cancer and lymph node dissection may be omitted for low risk patients.

KLF4 is a transcription factor with divergent functions in different malignancies. We analyzed KLF4 expression and DNA methylation, and their clinical relevance and biological function in urothelial cancer.Immunohistochemistry and Sequenom™ MassARRAY® were done to detect the expression and promoter methylation of KLF4 in urothelial cancer tissues. The association of the recurrence-free survival rate and decreased KLF4 or KLF4 methylation status was analyzed by the Kaplan-Meier method, Cox regression analysis and ROC assay. Lentivirus based KLF4 over expression and dsRNA mediated knockdown were used to detect KLF4 functions in urothelial cancer in vitro and in vivo.KLF4 was down-regulated in urothelial cancer due to promoter hypermethylation. Each correlated with recurrence-free survival in patients with nonmuscle invasive bladder cancer after transurethral resection of bladder cancer, which potentiates them as valuable predictive biomarkers for early recurrence. Moreover, in and ex vivo experiments showed that KLF4 suppressed urothelial cancer cell growth, migration and invasion inhibited the epithelial-to-mesenchymal transition.KLF4 may function as a tumor suppressor gene in urothelial cancer since down-regulation of KLF4 by promoter hypermethylation would promote cancer progression. In addition, decreased expression of KLF4 or its promoter hypermethylation may have predictive value for early recurrence in patients with nonmuscle invasive bladder cancer.

We determined the association of the proliferation marker Ki-67 with pathological parameters and oncologic outcomes in patients with high grade upper tract urothelial carcinoma.Immunohistochemical staining for Ki-67 was done prospectively in 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high grade upper tract urothelial carcinoma. Data were compared based on Ki-67 status (normal vs over expressed). Survival was assessed by the Kaplan-Meier method. Cox regression analysis was done to identify independent predictors of time dependent outcomes.Median patient age was 70.0 years and median followup was 22.0 months (range 1 to 77). Overall, 30.2% of the population experienced recurrence and 24.8% died of upper tract urothelial carcinoma. Organ confined disease (T2 or less and lymph node negative), lymphovascular invasion and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients, respectively. Ki-67 was over expressed in 73.3% of patients and associated with adverse pathological features. Patients with over expressed Ki-67 had significantly worse recurrence-free survival (43.2 vs 69.0 months, p = 0.006) and cancer specific survival (48.9 vs 68.9 months, p = 0.031) than patients with normal Ki-67. Patients with nonmetastatic disease similarly had worse recurrence-free survival (40.7 vs 71.8 months, p = 0.003) and cancer specific survival (41 months vs not attained, p = 0.008) for over expressed vs normal Ki-67. After adjusting for the effects of organ vs nonorgan confined disease Ki-67 over expression was an independent predictor of recurrence-free survival in the total cohort (HR 4.3, p = 0.05) and in patients with nonmetastatic disease (HR 8.5, p = 0.038).Ki-67 over expression was associated with adverse pathological features in cases of upper tract urothelial carcinoma. It was also an independent predictor of recurrence-free survival in patients with high grade upper tract urothelial carcinoma.

Purpose To analyze the association between the use of diagnostic ureteroscopy (URS) and development of intra-vesical recurrence (IVR) in patients undergoing radical nephroureterectomy (RNU) for high risk upper tract urothelial cancer. Methods A systematic review of the published data was performed up to December 2016 using multiple search engines to identify eligible studies. A formal meta-analysis was conducted for studies comparing patients who underwent URS before RNU to those with did not. HRs with their 95% CIs from each study were used to calculate pooled HRs. Pooled estimates were calculated using a fixed-effects or random-effects model according to heterogeneity. Statistical analyses were performed using RevMan, version 5. Results Seven studies were included in the systematic review, but only six of were deemed fully eligible for meta-analysis. Among the 2,382 patients included in the meta-analysis, 765 underwent diagnostic URS prior to RNU. All examined studies were retrospective, and the majority examined Asian populations. The IVR rate ranged from 39.2% to 60.7% and from 16.7% to 46% in patients with and without prior URS, respectively. At pooled analysis, a statistically significant association was found between occurrence of URS prior to RNU and IVR (HR=1.56; 95% CI 1.33 to 1.88; p < 0.001). There was not heterogeneity in the observed outcomes according to the I2 statistic of 2% (p = 0.40). Conclusions Within the intrinsic limitations of this type of analysis, these findings suggest a significant association between the use of diagnostic URS and higher risk of developing IVR after RNU. Further research is this area should be encouraged to further investigate the possible causality behind this association and it potential clinical implications. This article is protected by copyright. All rights reserved.

International audience; PURPOSE: We assessed the prognostic value of extranodal extension and other lymph node parameters in a large multicenter cohort of patients with lymph node metastasis after radical nephroureterectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of 222 patients with lymph node metastasis treated with radical nephroureterectomy for upper tract urothelial carcinoma without neoadjuvant therapy. Each lymph node metastasis was microscopically evaluated for extranodal extension. RESULTS: A median of 4 lymph nodes (IQR 8) was removed. Two lymph nodes (IQR 2) were positive. Lymph node density was 51.3% (IQR 71.7%). Overall 110 patients (49.5%) had extranodal extension, which was associated with more advanced pT stage (p = 0.026). On multivariable analysis extranodal extension was associated with disease recurrence (p = 0.01) and cancer specific mortality (p = 0.013). When stratified by a 30% cutoff, lymph node density was associated with disease recurrence and cancer specific mortality on univariable but not multivariable analysis (p = 0.048 and 0.049, respectively). Adding extranodal extension to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p

Upper urinary tract urothelial carcinoma is rare. Evidence shows that it behaves differently from urothelial bladder tumors. A polymorphism located at the T allele of rs9642880 on chromosome 8q24 is linked to an enhanced risk of bladder tumors. We explored the association of this polymorphism with susceptibility to upper urinary tract urothelial carcinoma.We genotyped the constitutional DNA of 261 patients with upper urinary tract urothelial carcinoma and 261 healthy controls matched for age, gender, smoking habit and ethnicity. Polymorphisms at rs9642880 on chromosome 8q24 were determined using the 5' nuclease polymerase chain reaction method with specific primers and probes. Frequencies were compared between cases and controls. Genotypes were in Hardy-Weinberg equilibrium for cases and controls.Mean patient age was 68.7 years. The T/T genotype resulted in a significantly higher risk of upper urinary tract urothelial carcinoma (OR 1.72, 95% CI 1.1-2.8, p = 0.028). Using single polytomous regression analysis the T/T genotype was also associated with aggressive tumors when stratified by stage (p = 0.003), or grade G2 (p = 0.04) or G3 (p = 0.01).Our results strongly suggest that the T/T rs9642880 genotype is a risk factor for upper urinary tract urothelial carcinoma, as previously shown for bladder tumors. In contrast to bladder carcinoma, for upper urinary tract urothelial carcinoma the T/T genotype is associated with aggressiveness.

We describe laparoscopic management of multiple ureteral polyps and our objective initial experience in children.We used laparoscopic polypectomy and pyeloureterostomy to treat 13 patients (15 ureters) diagnosed with hydronephrosis caused by multiple ureteral polyps between August 2006 and November 2010. Mean patient age was 11.4 years. The polyps were left sided in 9 patients, right sided in 2 and bilateral in 2. Hydronephrosis was mild in 9 cases, moderate in 4 and severe in 2. Postoperative followup consisted of ultrasound and excretory urography.A total of 12 patients were successfully treated with laparoscopy, while 1 patient with bilateral polyps required conversion to open surgery. Mean polyp length was 4.5 cm. Mean operative time in the unilateral cases was 121 minutes. The bilateral polyps were operated on simultaneously, with a surgical time of 185 minutes. Mean hospital stay was 3.5 days. Followup ranged from 6 to 26 months. In 1 patient obstruction of the temporary Double-J® stent developed 1 week postoperatively due to the deposition of urinary salts. No recurrent polyps were seen on followup B-mode ultrasound or excretory urography.Laparoscopic management of multiple ureteral polyps in children can be considered a safe and effective minimally invasive surgical option. However, further studies with larger cohorts are needed to confirm this finding.

Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma. While the risk has been quantified, to our knowledge there is no description of how this population of patients with Lynch syndrome and upper urinary tract cancer differs from the general population with upper urinary tract cancer.We obtained retrospective data on a cohort of patients with Lynch syndrome from the Hereditary Cancer Center in Omaha, Nebraska and compared the data to those on a control general population from western Sweden. These data were supplemented by a new survey about exposure to known risk factors.Of the patients with Lynch syndrome 91% had mutations in MSH2 rather than in MSH1 and 79% showed upper tract urothelial carcinoma a mean of 15.85 years after prior Lynch syndrome-type cancer. Median age at diagnosis was 62 years vs 70 in the general population (p0.0001). Only half of our patients had a significant smoking history and the male-to-female ratio was 0.95. Of patients with Lynch syndrome 51% had urothelial carcinoma in the ureter while it occurred in the renal pelvis in 65% of the general population (p = 0.0013). Similar numbers of high grade tumors were found in the Lynch syndrome and general populations (88% and 74%, respectively, p = 0.1108).Upper urinary tract tumors develop at a younger age and are more likely to be in the ureter with an almost equal gender ratio in patients with Lynch syndrome. It has high grade potential similar to that in the general population.

Fluorescence in situ hybridization is gaining popularity for transitional cell carcinoma screening. We determined the accuracy of fluorescence in situ hybridization for identifying upper tract transitional cell carcinoma.A retrospective review of our upper tract transitional cell carcinoma database from 2005 to 2008 identified 35 patients with upper tract transitional cell carcinoma who submitted voided urine specimens for fluorescence in situ hybridization at commercial laboratory during a routine office visit. Each patient was evaluated endoscopically in the operating room within 3 months of sampling. Suspicious lesions were biopsied and treated. Transitional cell carcinoma in the lower or upper tract was proved by direct visualization, positive biopsy or upper tract cytology read as positive or highly suspicious for malignancy.Of the patients 35 satisfied study inclusion criteria. A total of 67 fluorescence in situ hybridization specimens were submitted. Upper tract transitional cell carcinoma was identified on 51 operative evaluations, of which 23 showed concurrent bladder tumor. For all encounters the sensitivity of fluorescence in situ hybridization was 56% and specificity was 80%. Sensitivity for low and high grade lesions was 68% and 67%, respectively. Only upper tract tumors were noted in 28 patients, in whom there were 2 false-positive and 13 false-negative voided fluorescence in situ hybridization results. In these cases sensitivity was 54% and specificity was 78% compared to the 18% sensitivity and 100% specificity of bladder cytology. Sensitivity for low and high grade upper tract transitional cell carcinoma was 60% and 50%, respectively.Voided fluorescence in situ hybridization has become an adjunct for bladder transitional cell carcinoma surveillance. However, it has limited value for upper tract tumor surveillance.

We evaluated the value of hydronephrosis, ureteroscopic biopsy grade and urinary cytology to predict advanced upper tract urothelial carcinoma.We reviewed the charts of 469 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy or distal ureterectomy. Complete data on hydronephrosis (present vs absent), ureteroscopic grade (high vs low) and urinary cytology (positive vs negative) were available in 172 patients. The outcome was muscle invasive (pT2-pT4) or nonorgan confined (pT3 or greater, or lymph node metastasis) upper tract urothelial carcinoma.Of the patients 92 (54%) had hydronephrosis, 74 (43%) had high grade disease on ureteroscopic biopsy and 137 (80%) had positive cytology. On univariate analysis hydronephrosis (p0.001), high ureteroscopic grade (p0.001) and positive cytology (p = 0.03) were associated with muscle invasive and nonorgan confined disease. On multivariate analysis adjusting for tumor site, gender and age hydronephrosis and high ureteroscopic grade were associated with muscle invasive carcinoma (HR 12.0 and 4.5, respectively, each p0.001) but cytology was not (HR 2.3, p = 0.17). However, all 3 variables were independently associated with nonorgan confined disease (HR 5.1, p0.001; HR 3.9, p0.001; and HR 3.1, p = 0.035, respectively). Combining these 3 tests incrementally improved the prediction of upper tract urothelial carcinoma stage. Abnormality of all 3 tests had 89% and 73% positive predictive value for muscle invasive and nonorgan confined upper tract urothelial carcinoma, respectively, but when all tests were normal, the negative predictive value was 100%.Preoperative evaluation for hydronephrosis, ureteroscopic grade and cytology can identify patients at risk for advanced upper tract urothelial carcinoma. Such knowledge may impact surgery choice and extent as well as the need for perioperative chemotherapy regimens.

We assessed the efficacy of prophylactic intravesical chemotherapy for primary upper urinary tract urothelial cancer after nephroureterectomy during long-term followup.From January 1985 to June 2007, 196 patients with primary upper urinary tract urothelial cancer were included in this study. Patients were divided into group 1-31 who received intravesical epirubicin instillation, group 2-27 who received intravesical mitomycin C instillation and group 3-138 who did not receive prophylactic instillation after nephroureterectomy. We compared the bladder tumor recurrence rate, number of recurrence episodes, time to first bladder tumor recurrence, tumor type, percent of patients with cystectomy and percent who died of urothelial cancer, and the recurrence-free survival rate.Of the 196 patients 73 had subsequent bladder recurrence at a mean followup of 55.6 months. There were no significant differences in recurrence type, mean number of bladder tumor recurrences, percent of patients with cystectomy and the cancer specific survival rate. The bladder recurrence rate was lower in group 1 and 2 than in group 3. Mean time to first bladder tumor recurrence was longer in groups 1 and 2. Kaplan-Meier curves of recurrence-free survival rates were significantly increased in groups 1 and 2.Intravesical instillation of epirubicin or mitomycin C appears to be well tolerated and effective for preventing bladder recurrence and prolonging time to first bladder recurrence. Patients should receive prophylactic intravesical chemotherapy after nephroureterectomy.

It is debatable whether traditionally used excretory urography or the recently introduced multidetector computerized tomography urography is more accurate for diagnosing upper urinary tract transitional cell carcinoma. We compared accuracy measures of both methods for diagnosing upper urinary tract transitional cell carcinoma in adult patients with hematuria.We retrospectively analyzed consecutive adult patients with hematuria undergoing excretory urography and multidetector computerized tomography urography before any surgery, intervention or treatment from April 2004 to December 2006 in our hospital. The presence of upper urinary tract transitional cell carcinoma on excretory urography and multidetector computerized tomography urography was reviewed independently by 2 uroradiologists who were blinded to clinical information and other imaging results. Final diagnosis of upper urinary tract transitional cell carcinoma was confirmed by histological results. Measures of the diagnostic accuracy of excretory urography and multidetector computerized tomography urography for upper urinary tract transitional cell carcinoma were calculated and compared with reference to the final diagnosis.Of 34 men and 26 women with hematuria (mean age 60.73 +/- 12.95 years) 19 (31.7%) had a final diagnosis of 24 upper urinary tract transitional cell carcinomas. The sensitivity, specificity and accuracy of excretory urography were 0.750, 0.860 and 0.849, respectively. In contrast, the sensitivity, specificity and accuracy of multidetector computerized tomography urography were 0.958, 1.000 and 0.996, respectively. Overall the area under the receiver operating characteristic curve for multidetector computerized tomography urography was significantly larger than that for excretory urography (0.978 vs 0.815, p = 0.005).Multidetector computerized tomography urography is more sensitive, specific and accurate than excretory urography in the diagnosis of upper urinary tract transitional cell carcinoma in adult patients with hematuria. Therefore, multidetector computerized tomography urography rather than excretory urography should be the first choice noninvasive imaging modality for diagnosing upper urinary tract transitional cell carcinoma.

We investigated whether tumor location has independent prognostic significance in upper tract transitional cell carcinoma cases and which factor determines it.We reviewed data on 122 renal pelvis and 102 ureteral tumor cases, including the recurrence pattern. Tumor location and other clinicopathological variables were evaluated regarding cancer specific and recurrence-free survival. Stage pT3 tumors were stratified into those invading renal parenchyma or peripelvic/periureteral fat.Overall 5-year cancer specific survival and recurrence-free survival rates were 77.0% and 71.6%, respectively, at a mean followup of 60.7 months. Of the clinicopathological parameters T stage was the most significant prognosticator of the survival rate, while nodal involvement, high grade and ureteral tumor location were also significant for lower survival rates. Stratification analysis for matching pathological stage revealed that, while survival rates were similar in the renal pelvis and ureteral tumor groups at stage pT2 or less, renal pelvic tumors were associated with significantly higher survival rates than ureteral tumors for stage pT3. Specifically renal pelvic tumors invading the renal parenchyma were associated with a lower local failure rate, and higher cancer specific and recurrence-free survival rates than tumors invading peripelvic or periureteral fat, ie 77.5% vs 49.7% 5-year cancer specific survival and 75.6% vs 32.0% 5-year recurrence-free survival (p = 0.014 and 0.003, respectively).Tumor location is an independent prognostic factor for pT3 upper tract transitional cell carcinoma. The overall better prognosis of renal pelvic tumors was mainly attributable to pT3 tumor outcomes, specifically lesions invading the renal parenchyma. These findings may be due to the protective role of thick renal parenchyma against local tumor spread.

We studied the long-term prognosis, and evaluated the predictors of disease specific and recurrence-free survival in a large cohort of patients who had undergone radical nephroureterectomy for primary transitional cell carcinoma of the ureter.From January 1990 to December 2006, 145 patients with primary ureteral transitional cell carcinoma treated with nephroureterectomy and bladder cuff removal at our institution were included in the study. The medical records of these patients were reviewed retrospectively. The clinical and histopathological data were analyzed to evaluate the prognostic predictive factors. Univariate and multivariate statistical analyses were performed.The 5-year disease specific survival rates of stage pTa/Tis/T1, pT2, pT3 and pT4 were 94.6%, 81.8%, 47.4% and 0%, respectively. The 5-year recurrence-free survival rates according to tumor grade were 68.4% for low grade and 35.7% for high grade disease. Of the 145 patients subsequent bladder tumors developed in 38 (26.2%), local recurrence developed in 11 (7.6%) and metachronous contralateral upper urinary tract tumor developed in 3 (2.1%). Most patients had subsequent tumor recurrence within the first year after radical surgery. On univariate and multivariate analyses tumor stage, tumor grade, severity of chronic renal disease, synchronous bladder tumor and hematuria were the significant prognostic variables predicting disease specific and recurrence-free survival.Advanced tumor and chronic renal disease stages were significantly associated with a worse prognosis in patients with primary ureteral transitional cell carcinoma who had undergone radical nephroureterectomy. With regard to tumor recurrence, advanced tumor stage, high tumor grade and synchronous bladder tumor were independent risk factors.

We analyzed the diagnostic value of multidetector computerized tomography urography for transitional cell carcinoma in patients with gross hematuria.All consecutive adult patients with gross hematuria who underwent multidetector computerized tomography urography in a 23-month period were prospectively enrolled. Transitional cell carcinoma and its location on multidetector computerized tomography urography were recorded at a prospective reading with knowledge of the pertinent history and at a retrospective reading while blinded to all information. Histological evidence of transitional cell carcinoma served as the gold standard for final diagnosis. Patients who were lost to followup, refused biopsy/surgery for clinically suspicious neoplasms or had negative diagnostic evaluation but a followup of less than 1 year were excluded from study. We analyzed the diagnostic value of multidetector computerized tomography urography for transitional cell carcinoma by location with reference to final diagnosis.A total of 139 patients were eligible for study, of whom 24 were excluded from analysis. There was no difference in demographic features between included and excluded patients. Of the 115 included patients 60 had a final diagnosis of a total of 77 transitional cell carcinomas in the renal pelvis, ureter or bladder. Overall sensitivity, specificity and accuracy of multidetector computerized tomography urography for diagnosing transitional cell carcinoma were 0.857, 0.980 and 0.963 at the retrospective reading, and 0.961, 0.988 and 0.984 at the prospective reading, respectively. Multidetector computerized tomography urography had the highest accuracy for diagnosing renal transitional cell carcinoma and the lowest sensitivity for detecting ureteral transitional cell carcinoma.Multidetector computerized tomography urography is an accurate, noninvasive imaging modality for diagnosing transitional cell carcinoma in patients with gross hematuria. However, careful assessment of the ureter for multidetector computerized tomography urography is required for detecting ureteral transitional cell carcinoma.

The defined risk of upper tract recurrence in published series ranges from 2% to 6%, with most recurrence reported within 2 to 3 years of surgery. However, these recurrence rates are based on statistical methodology that does not take censoring into account. We used landmark time analysis to determine whether the risk of upper tract recurrence changes over time.We present a retrospective institutional review board approved review of 1,329 patients who underwent radical cystectomy from 1990 to 2004. Upper tract recurrence was defined as any radiographic, endoscopic or pathologically proven recurrence in the kidney or ureter. Cumulative incidence of upper tract recurrence was estimated by accounting for death without recurrence as a competing risk. Landmark analyses were used to estimate the probability of upper tract recurrence within the next 3 years if recurrence-free at various times after surgery.A total of 80 patients experienced upper tract recurrence. Median followup for patients alive and recurrence-free was 38 months. The 3 and 5-year cumulative incidence of upper tract recurrence was 4% (95% CI 3, 6) and 7% (95% CI 5, 8), respectively. Landmark time analysis showed the 3-year cumulative incidence of upper tract recurrence remained 4% to 6% even at 4 years after radical cystectomy. Any ureteral involvement at radical cystectomy (including carcinoma in situ) portends a significantly higher risk of upper tract recurrence.The incidence for upper tract recurrence was 4% at 3 years and 7% at 5 years. However, the 3-year risk of upper tract recurrence remained around 4% to 6% at any point measured up to 4 years after radical cystectomy and, therefore, did not change over time. This indicates the critical importance of long-term vigilance for upper tract recurrence following radical cystectomy.

We determined the impact of the extent of regional lymphadenectomy on survival in patients with urothelial carcinoma of the upper urinary tract.Between January 1989 and January 2006, 169 patients with nonmetastatic urothelial carcinoma of the upper urinary tract underwent curative surgery. We previously reported the primary sites of nodal metastases in urothelial carcinoma of the upper urinary tract. Nodal sites where the incidence of metastases was 30% or more were considered regional lymph nodes. When all primary sites were resected, this was considered complete lymphadenectomy. Regional lymphadenectomy without the removal of all primary sites was considered incomplete lymphadenectomy. We retrospectively analyzed the influence of the extent of lymphadenectomy on patient survival.A total of 45 patients (26.6%) underwent complete lymphadenectomy. Lymphadenectomy was performed in an additional 36 patients (21.3%) but it was incomplete. Lymphadenectomy was not performed in 88 patients. Cancer specific survival did not significantly differ between the groups when all patients were analyzed. However, patient survival significantly depended on the extent of lymphadenectomy when we focused on patients with T stage pT3 or higher. Patient survival was likely to improve when the number of lymph nodes removed increased. Multivariate analysis showed that complete lymphadenectomy was a significant prognostic factor for cancer specific survival (p = 0.009) as well as T stage (pT3 or less p = 0.0004) and tumor grade (G3 p = 0.0001).Although further investigation is required to make a definite conclusion, the extent of lymphadenectomy may significantly influence its therapeutic effect, especially for patients with advanced disease.

Stage 3 upper urinary tract transitional cell carcinoma is a heterogeneous disease including different tumor locations (pelvis vs ureter) and invasion patterns (renal parenchyma, peripelvic fat and periureteral fat). Unfortunately the outcomes of patients with pT3 disease with different invasion pattern are largely unknown. This study presents the clinical outcome of patients with pT3 disease with upper urinary tract transitional cell carcinoma.We retrospectively reviewed the medical records of all patients with pT3 disease with upper urinary tract transitional cell carcinoma. Four patient groups were classified according to tumor location and tumor invasion pattern. Prognostic factors including age, gender, tumor grade, tumor size, tumor number, tumor location and microscopic finding of vascular invasion were analyzed with respect to disease recurrence and survival.A total of 72 patients were included in this study. The most common complaint and tumor relapse pattern were painless gross hematuria and distant metastasis, respectively. Patients with pT3 disease with superficial parenchymal invasion had better disease-free and recurrence-free survival than the other 3 groups. Initial tumor location (p = 0.02) and vascular invasion (p = 0.02) were independent factors for disease-free survival, and vascular invasion (p = 0.001) was the only predictive factor for recurrence-free survival.The present study demonstrated that patients with pT3 disease with superficial parenchymal invasion should be considered to have lower stage disease, and that vascular involvement is the only independent prognostic factor for patients with pT3 disease for disease-free and recurrence-free survival. Systemic adjuvant therapy should be recommended for patients with pT3 disease with vascular involvement.

We reviewed the clinical outcome for patients who underwent decompression of malignant ureteral obstruction by analyzing potential prognostic factors, technical success, complication rates and days spent in hospital.Retrospective analysis of 102 patients who underwent decompression for malignant ureteral obstruction from 1991 to 2003 was performed. Data on overall survival, prognostic factors, technical failure, complications and days of hospitalization after decompression were examined.Median overall survival was 6.8 months (95% CI 4.8-9.3) and the overall survival rate at 12 months was 29% (95% CI 21%-39%). Univariate analyses found inferior overall survival associated with patients having metastases (p=0.041), undergoing nephrostomy (p=0.046), prior treatment for cancer (p=0.024) and diagnosis of malignant ureteral obstruction in previously established malignancy (p=0.043). After multivariate analysis poor prognostic factors were presence of metastases (p=0.020) and diagnosis of malignant ureteral obstruction in previously established malignancy (p=0.039). Unfavorable cohorts with 3 or 4 unfavorable baseline risk factors had an inferior overall survival (p=0.008) with 12-month overall survival rates of 12% to 19%. Initial decompression of malignant ureteral obstruction failed in 6% of patients (95% CI 2%-12%) and complications were experienced by 53% (95% CI 43%-63%). Patients were more likely to experience a complication if they had therapy after decompression (p=0.03). The median percentage of their remaining lifetime spent in hospital was 17.4% (range 0.21% to 100%).The overall survival of patients with malignant ureteral obstruction remains poor. Prognostic factors for decreased overall survival and prolonged hospital stay have been identified. Although the technical success of decompression has improved the subsequent complication rate is still high.