Tract Urothelial Cancer Research Articles

De Ritis Ratio (AST/ALT) as a Significant Prognostic Factor in Patients With Upper Tract Urothelial Cancer Treated With Surgery.

We investigated the clinical prognostic value of preoperative De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) on postsurgical survival outcomes in patients with upper tract urothelial cancer (UTUC). We retrospectively analyzed the data of 623 patients who underwent radical nephrouretectomy for UTUC. Multivariate regression tests were performed to identify possible associations between adverse pathologic events and AST/ALT. The risk of postoperative progression and survival were tested using Kaplan-Meier analyses and Cox proportional hazards models. According to the receiver operator characteristic curve of AST/ALT for cancer-specific mortality, patients with AST/ALT value≥1.5 were regarded as the high AST/ALT group, and the remaining patients formed the low AST/ALT group. In Kaplan-Meier analyses, the high AST/ALT group showed worse progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (all P< .001). Elevated AST/ALT was associated with higher T stage (hazard ratio [HR], 1.577; 95% confidence interval [CI], 1.077-2.311; P= .033) and higher cellular grade (HR, 1.538; 95% CI, 1.034-2.287; P= .041) in multivariate regression tests. In multivariate Cox analyses, high AST/ALT was revealed as an independent predictor of PFS (HR, 2.335; 95% CI, 1.633-3.340; P< .001), CSS (HR, 2.550; 1.689-3.851; P< .001), and overall survival (HR, 2.069; 95% CI, 1.409-3.038; P< .001). Elevated preoperative AST/ALT was a significant predictor of worse postoperative survival in patients surgically treated for UTUC. Further large prospective studies are needed for better understanding of the prognostic value of preoperative AST/ALT.

Detecting primary upper tract urothelial cancer with by whole body FDG PET/CT

Detecting primary upper tract urothelial cancer with by whole body FDG PET/CT

Survival Comparison Between Endoscopic and Surgical Management for Patients With Upper Tract Urothelial Cancer: A Matched Propensity Score Analysis Using Surveillance, Epidemiology and End Results-Medicare Data

To determine survival differences among patients receiving endoscopic vs surgical management for upper tract urothelial carcinoma (UTUC). Using Surveillance, Epidemiology and End Results-Medicare data, patients diagnosed with nonmuscle-invasive, low-grade UTUC as their first cancer diagnosis between 2004 and 2009 were identified. Receipts of endoscopic and surgical interventions were assessed, and patients were separated into surgical or endoscopic management cohorts. Two-to-one propensity score analysis was performed to control for baseline characteristics between groups. The endoscopic management (n = 151) and matched surgical management (n = 302) groups demonstrated no significant differences in age, gender, race, marital status, Charlson comorbidity index, or year of diagnosis. Endoscopic management was an independent and significant predictor of all-cause and cancer-specific mortality (hazard ratio 1.6 for overall survival [OS], hazard ratio 2.1 for cancer-specific survival [CSS]). Kaplan-Meier estimated survival was significantly lower for endoscopic management, with both OS and CSS curves diverging at approximately 24-36 months. A subset of patients initially receiving endoscopic management went on to receive surgical intervention (80/151 = 53%) at a median of 8.8 months from diagnosis. For these patients, Kaplan-Meier-estimated CSS was not significantly different from those who continued with only endoscopic management, and remained significantly lower than patients who received upfront surgery. Although initial survival outcomes (first 24 months) are similar for endoscopic and surgical management of nonmuscle-invasive, low-grade UTUC, both CSS and OS are significantly inferior for the endoscopic management group in the longer term. Furthermore, transition from initial endoscopic management to surgical intervention appears to have limited impact on survival.

Acute toxicity data from POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer.

e16138Background: The POUT trial compares surveillance (surv) with immediate chemotherapy (CT), following nephroureterectomy (NU) (CRUK/11/027). The primary endpoint is disease free survival. Secon...

ECOG 8141: A prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high grade upper tract urothelial carcinoma.

TPS4585Background: Upper tract urothelial cancer (UTUC) accounts for approximately 5% of all urothelial cancers. At presentation, 30% of patients demonstrate invasive and/or locally advanced diseas...

The impact of pathologic characteristics (lymphovascular invasion/squamous differentiation) on the efficacy of adjuvant chemotherapy for patients with upper tract urothelial cancer.

e16139Background: The benefit of adjuvant chemotherapy (AC) for upper tract urothelial cancer (UTUC) is controversial. Pathologic characteristics such as lymphovascular invasion (LVI) and squamous ...

Variant isoforms of CD44 expression in upper tract urothelial cancer as a predictive marker for recurrence and mortality

PurposeThe variant isoforms of CD44 (CD44v), which has been associated with treatment resistance and tumor recurrence, are contributed to the feature of some of the new cell surface markers for cancer stem cells. The aim of this study is to address the prognostic significant of CD44v expression in upper tract urothelial cancer (UTUC). Materials and methodsWe retrospectively analyzed the medical records of 110 patients treated surgically for≥pT2 UTUC. To determine the biological significance of CD44v in UTUC, we examined the immunohistochemical expression of CD44v9 and its association with clinical features and oncological outcomes. ResultsDuring the mean follow-up of 4.8 years, tumor recurrence, including local and distant metastasis, was observed in 57 patients (51.8%), and 42 patients (38.2%) died of the disease. The incidence of ureter cancers was significantly higher in patients expressing CD44v9. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. Kaplan-Meier curves revealed that cancer-specific survival and recurrence-free survival rates were significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.032 and P = 0.038, respectively). A multivariate analysis identified the expression of CD44v9 as one of the independent risk factors for cancer-specific survival (P = 0.040, hazard ratio = 2.67) in addition to tumor grade G3, and also for recurrence-free survival (P = 0.028, hazard ratio = 2.33), in addition to tumor grade G3 and lymphovascular invasion. ConclusionsThe expression of CD44v9 may be a new biomarker of malignant potential in muscle invasive UTUC and provide additional prognostic information in patients with UTUC.

AB063. Comparisons of prognosis between urothelial carcinoma of the upper urinary tract and bladder with pT3-4 diseases

ObjectiveTo compare the prognosis of locally advanced upper tract urothelial carcinoma (UTUC) and bladder cancer (BC) in patients treated with radical surgeries.MethodsA retrospective analysis of the clinicopathological data of 228 consecutive UTUC patients and 174 BC patients treated by radical surgeries from 2000 to 2012 at a high-volume center in China was conducted. Kaplan-Meier method and Cox regression were used to compare overall survival (OS) and cancer-specific survival (CSS) and to find prognostic factors.ResultsBC were associated with male sex (P<0.001), high grade (P=0.002), multifocality (P<0.001), positive lymph node (P=0.002), no hydronephrosis (P<0.001) and open surgical approach (P<0.001). UTUC have statistically significant better 5-year CSS rate (61.0% vs. 49.8%, P=0.008) and OS rate (58.3% vs. 37.4%, P<0.001) than BC. Bladder tumor location [UTCU vs. BC: hazard ratio (HR) =0.703 and HR =0.462] and positive lymph node status (HR =1.919 and HR =1.667) were independent risk factors of cancer-specific death and overall mortality, respectively.ConclusionsOur data suggest that locally invasive urothelial carcinomas (UC) behave differently in the upper and lower urinary tracts. UTUC has a better prognosis than BC when stage and grade are considered simultaneously and lymph node involvement has significant influences on clinical outcomes of urothelial carcinoma.

803 Risk stratification model for lymphovascular invasion, pathological T stage, lymph node involvement, and c-reactive protein predicts high-risk patients - who are candidate for adjuvant chemotherapy in upper urinary tract urothelial cancer

803 Risk stratification model for lymphovascular invasion, pathological T stage, lymph node involvement, and c-reactive protein predicts high-risk patients - who are candidate for adjuvant chemotherapy in upper urinary tract urothelial cancer

Editorial Comment from Dr Miyata and Dr Sakai to Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi-institutional nationwide case series study of the Japanese Urological Association.

Editorial Comment from Dr Miyata and Dr Sakai to Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi-institutional nationwide case series study of the Japanese Urological Association.

Editorial Comment from Dr Sakano and Dr Matsuyama to Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi‐institutional nationwide case series study of the Japanese Urological Association

Editorial Comment from Dr Sakano and Dr Matsuyama to Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi‐institutional nationwide case series study of the Japanese Urological Association

The hotspot mutational landscape of upper tract and bladder urothelial cancers and correlation to survival.

466 Background: The prevalence of potentially targetable molecular mutations in urothelial carcinoma of the upper tract and bladder carcinoma are beginning to emerge. Important differences of molecular alterations may exist between upper tract and bladder primary tumors necessitating different treatment approaches and drug development strategies for these patients. Methods: All patients with urothelial carcinoma at UT MD Anderson who had undergone the CLIA-certified 50 gene panel utilizing next generation sequencing for detection of hotspot mutations were retrospectively reviewed. The prevalence of mutations was tabulated and compared between upper tract and bladder primary tumor locations using the Fisher’s exact test. Survival comparisons were calculated using the Kaplan-Meier technique and the Log Rank Test. Results: 136 patients with urothelial carcinoma were included in the analysis of which 41 were upper tract and 95 had bladder primary tumors. Of the 136 patients, 132 had de novo or developed metastatic/recurrent disease. The most prevalent mutations in the upper tract primary cohort included FGFR3, TP53, EGFR, FBXW7, PIK3CA, and KRAS. The most prevalent mutations in the bladder primary tumors were TP53, PIK3CA, RB1, FGFR3, HRAS, KRAS, BRAF, and FBXW7. In both upper tract and bladder tumors, a mutation in FGFR3 was nearly mutually exclusive for having a TP53 mutation. Compared to bladder primary tumors, upper tract tumors were more likely to have an FGFR3 mutation (36.5% vs. 7.4%, p &lt; 0.0001), while the prevalence of TP53 (34% vs. 49%) and or a mutation in PIK3CA, HRAS, or KRAS (12.2% vs. 20.8%) was not significantly different. In the 132 patients with metastatic disease, the presence of a mutation in PIK3CA, HRAS, or KRAS was associated with inferior survival (HR 2.342, 95% CI: 1.32-8.67, p = 0.012), while the presence of an FGFR3 or TP53 mutation was not associated with a statistically different survival when compared to patients with wild type mutational status. Conclusions: Patients with upper tract and bladder primary sites have different molecular mutation rates. Understanding how these mutations in differing sites affect tumor biology may have important clinical implications.

Predictive models for improved prognostication and selection of neoadjuvant and adjuvant systemic chemotherapy in upper tract urothelial cell carcinoma.

456 Background: Chemotherapy is still underutilized in management of upper tract urothelial carcinoma (UTUC). We created pre and post-operative predictive tools combining independent prognostics to guide selection of patients for neoadjuvant and adjuvant chemotherapy. Methods: From the UTUC collaboration database (1,453 patients who underwent radical nephroureterectomy [RNU] at 13 academic institutions); a preoperative predictive model was created using 659 patients in whom all preoperative prognostic variables were available and a post-operative model was created using 586 patients with non-metastatic/ high-grade UTU. After multivariable survival analyses, a backward step-down selection process was applied to create a preoperative nomogram. Internal validation was performed using 200 bootstrap resamples. For the postoperative model, TALL score was created based on the sum of the independent prognostic variables. Results: Preoperative model: Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer. Postoperative model: TALL score (1-7) was the sum of T ( ≤ T1 = 1, T2 = 2, T3 = 3 and T4 = 4), A (papillary = 0 and sessile = 1), LVI (absent = 0 and present = 1) and L (lymphadenectomy = 0 and no lymphadenectomy = 1). Five-year disease-free survival (DFS) and cancer-specific survival (CSS) were stratified into four risk categories according to the TALL score: low (TALL 0-2; 86 % DFS and 90 % CSS), intermediate (TALL = 3; 71 % DFS and 75 % CSS), high (TALL = 4; 57 % DFS and 58 % CSS) and very high risk (TALL ≥ 5; 34 % DFS and 38 % CSS) using Kaplan-Meier survival analyses. TALL score was externally validated in a single-center cohort of 85 UTUC patients. Conclusions: We developed validated multivariable prognostic tools for prediction of locally advanced UTUC and oncological outcomes after RNU for UTUC. These prediction models can be used for patient counseling, selection for neoadjuvant/adjuvant systemic therapies and design of clinical trials.

Variant isoforms of CD44 expression as predictive markers for mortality in surgically treated patients with locally advanced upper tract urothelial carcinoma.

388 Background: The variant isoforms of CD44 (CD44v), which are some of the new cell surface markers for cancer stem cells, have been associated with tumor growth, treatment resistance, and cancer death in several cancers. We investigated the role of CD44v8-10, which is a CD44v, on the clinical outcome of patients with advanced upper tract urothelial cancer (UTUC). Methods: The protein expression of CD44v8-10 was immunohistochemically evaluated using CD44v9 antibody, which detects immunogen of CD44v8-10, and investigated the association with clinical characteristics and outcome in surgical specimens obtained from 110 patients who had been treated with radical nephroureterectomy for ≥pT2 UTUC. The mean percentage of positive cancer cells stained with CD44v9 antibody in each tumor was estimated. Results: The median percentage of CD44v9 positivity was 5.50±7.74%. Patients were subsequently stratified into a CD44v9-positive group (n = 82) and a CD44v9-negative group (n = 28) based on a cut-off level of 5%. During the mean follow-up of 4.8 years, disease recurrence was observed in 49 patients (59.8%) in the CD44v9-positive group and in 8 patients (28.6%) in the CD44v9-negative group. The 5-year recurrence-free survival rates were 47.6% in the CD44v9-positive group and 66.6% in the CD44v9-negative group (p= 0.038). Multivariate analysis showed that tumor grade G3 (p= 0.005, HR = 3.77), the presence of lymphovascular invasion (p= 0.041, HR = 1.84), and CD44v8-10 expression (p= 0.028, HR = 2.33) were independent risk factors for disease recurrence. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. The 5-year cancer-specific survival rates were 57.8% in the CD44v9-positive group and 80.4% in the CD44v9-negative group (p= 0.032). The CD44v9 expression (p= 0.040, HR = 2.67) in addition to tumor grade G3 (p= 0.003, HR = 8.35) were independently associated with cancer death. Conclusions: The expression ofCD44v8-10 may be a new biomarker of malignant potential in locally advanced UTUC and could provide additional prognostic information in patients with UTUC.

Are we closer to seeing carcinoma in situ in the upper urinary tract?

IntroductionThere is observed increase in detection rate of upper urinary tract urothelial cancer worldwide. This is a result of improved imaging as well as implementation of novel technologies of direct visualization of upper urinary tract. Standard techniques still remain insufficient to diagnose flat urothelial lesions. Carcinoma in situ is characterized by flat disordered proliferation of urothelial cells with marked cytologic abnormality, which occur within one cell layer as well as full thickness urothelium and therefore requires a better technology to pick up early and subtle mucosal changes.Material and methodsThe review presents available diagnostic tools in detection of upper urinary tract urothelial cancer and their ability to depict carcinoma in situ. ResultsUreterorenoscopy is an investigation of choice as various promising techniques are under pilot investigations to enhance visualization of upper urinary tract carcinoma in situ. So far only photodynamic diagnosis has been reported to be as effective in detection of carcinoma in situ in the upper as within the lower urinary tract.ConclusionsAlthough we are close to see upper urinary tract carcinoma in situ all new promising diagnostic techniques still require further validation in multicenter clinical trials to indicate any change to current recommendations.

Superficial Urinary Bladder Cancer : Histopathological Findings , Recurrence Rate after Transurethral Resection and Association with Upper Urinary Tract Urothelial Cancer : A Retrospective Analysis

Superficial Urinary Bladder Cancer : Histopathological Findings , Recurrence Rate after Transurethral Resection and Association with Upper Urinary Tract Urothelial Cancer : A Retrospective Analysis

Concurrent bladder cancer in patients undergoing photodynamic diagnostic ureterorenoscopy: how many lesions do we miss under white light cystoscopy?

IntroductionThere is an ongoing debate on panurothelial changes in the upper and lower urinary tract as multifocal presentation of urothelial cancer is well recognised. Concurrent bladder cancer impacts the outcome of the upper urinary tract urothelial cancer treatment, while its detection still relies on the white light cystoscopy.Material and methodsWe retrospectively reviewed all patients who underwent photodynamic diagnostic ureterorenoscopy, choosing those who had synchronous bladder biopsies. Each patient received 20 mg/kg body weight of oral 5-Aminolevulinic acid around 3–4 hours before endoscopy. All procedures were performed by a single endourologist experienced in photodynamic diagnosis and flexible ureterorenoscopy.ResultsBetween July 2009 and June 2013, 69 patients underwent bladder biopsies at the time of photodynamic diagnostic endoscopic inspection of the upper urinary tract. In total, 43.5% (30/69) patients were found to have bladder lesions, of which 43.3% (13/30) were proven to be carcinoma in situ. White light inspection of the bladder missed bladder cancer in 16 (23.1%) patients, of which 12 were carcinoma in situ. There were 14 bladder cancer lesions missed under white light which were concomitant to the upper urinary tract urothelial cancer. Twelve (17.4%) patients developed minor complications relevant to the photosensitizer.ConclusionsThe study raises a concern about missing small bladder cancer/carcinoma in situ lesions on the initial diagnosis or in surveillance of the upper urinary tract urothelial cancer. Higher than previously reported, the rate of concomitant bladder cancer may suggest utilisation of photodynamic diagnosis to ensure the cancer free status of the bladder, but this needs to be ratified in a multi-institutional randomised trial.

Current status of minimally invasive surgery for treatment of renal stones and tumors using a flexible ureteroscopy

Received: March 30, 2016 Accepted: April 20, 2016 Corresponding author: Hwancheol Son E-mail: volley@snu.ac.kr © Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Retrograde intrarenal surgery (RIRS) has been accepted as the first-line option for surgical treatment of upper urinary tract pathologies including stones and tumors. With the development of surgical instruments with improved deflection mechanisms, visualization, and durability, RIRS has taken on an expanding role in treating urinary calculi located in the upper urinary tract, as it compensates for the shortcomings of shockwave lithotripsy and percutaneous nephrolithotomy. RIRS can also be considered a conservative treatment option for upper urinary tract urothelial cancer or as a means of intensive postoperative surveillance after radical treatment of urinary tract urothelial cancer. RIRS has a steep learning curve and various surgical techniques can be utilized during operations. The use of particular surgical instruments should take into consideration of the gain in surgical efficiency, decrease in complications, and cost-benefit tradeoff.

Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi-institutional nationwide case series study of the Japanese Urological Association.

To describe the nature of metastatic upper urinary tract urothelial cancer and determine the prognostic predictors or treatment modality associated with all-cause mortality. Within the nationwide case series study of the Japanese Urological Association, consisting of 1509 patients with urinary tract urothelial cancer diagnosed in 2005, we identified 102 patients with metastatic urinary tract urothelial cancer. Univariate and multivariate survival analyses identified prognostic outcome variables. Predominant sites of distant metastasis at diagnosis were the lungs (54.9%), distant lymph nodes (37.3%), bone (32.4%) and liver (19.6%). Of 102 patients, 70 patients (68.6%) died during the median follow-up period of 6 months, and the 2-year overall survival rate was estimated at 22%. The median survival time to all-cause mortality was 8.5 months (95% confidence interval 6.4-10.7 months). On multivariate analysis, independent predictive factors for all-cause mortality were age (hazard ratio 2.36, P = 0.015) and liver metastasis (hazard ratio 2.35, P = 0.037). Patients who received multimodal treatment including chemotherapy and surgery showed significantly better prognosis (median survival time 25.8 months) compared with patients treated with chemotherapy alone (median survival time 7.3 months) or best supportive care (median survival time 4.3 months). Age at diagnosis and the presence of liver metastasis seem to have an impact on survival of metastatic urinary tract urothelial cancer patients. Multimodal treatment including systemic chemotherapy and surgery might result in better prognosis in some of these patients.

Aristolochic acid exposure in Romania and implications for renal cell carcinoma.

Background:Aristolochic acid (AA) is a nephrotoxicant associated with AA nephropathy (AAN) and upper urothelial tract cancer (UUTC). Whole-genome sequences of 14 Romanian cases of renal cell carcinoma (RCC) recently exhibited mutational signatures consistent with AA exposure, although RCC had not been previously linked with AAN and AA exposure was previously reported only in localised rural areas.Methods:We performed mass spectrometric measurements of the aristolactam (AL) DNA adduct 7-(deoxyadenosin-N6-yl) aristolactam I (dA-AL-I) in nontumour renal tissues of the 14 Romanian RCC cases and 15 cases from 3 other countries.Results:We detected dA-AL-I in the 14 Romanian cases at levels ranging from 0.7 to 27 adducts per 108 DNA bases, in line with levels reported in Asian and Balkan populations exposed through herbal remedies or food contamination. The 15 cases from other countries were negative.Interpretation:Although the source of exposure is uncertain and likely different in AAN regions than elsewhere, our results demonstrate that AA exposure in Romania exists outside localised AAN regions and provide further evidence implicating AA in RCC.