Sessile Tumor Architecture Research Articles

Exploring Contribution of HMGA2 to the Aggressive Tumor Structure in Urothelial Carcinoma to Identify Prospective Clinical Applications

For patients with advanced upper tract urothelial carcinoma (UTUC), the five-year survival rate is approximately 20-40%. In previous real-world data analyses, we observed that UTUC patients with a sessile tumor architecture tend to exhibit more aggressive behavior and concurrently have poorer outcomes in terms of metastasis-free and cancer-specific survival. This suggests that tumor architecture may serve as a crucial prognostic factor for predicting outcomes. We utilized various tumor tissue specimens, categorizing them based on tumor architecture into papillary and sessile groups. RNA sequencing was used to analyze the two groups, and significant differences in the expression levels of high mobility group AT-hook 2 (HMGA2) were found. In the more aggressive sessile tumor architecture, HMGA2 exhibited higher expression levels. HMGA2 is currently known to participate in various biological processes, including the cell cycle, DNA damage repair, apoptosis, and epithelial-mesenchymal transition. Additionally, HMGA2 is abnormally regulated in several human cancers, such as lung, breast, ovarian, and bladder cancers. Elevated expression of HMGA2 is associated with a higher risk of tumor recurrence and cancer progression. Hence, we hypothesize that HMGA2 may regulate tumor cell epithelial-mesenchymal transition through the PI3K-Akt cell signaling pathway, influencing tumor architecture and cancer prognosis. Attempting to downregulate HMGA2 should theoretically enhance the effectiveness of chemotherapeutic drugs in achieving an anti-cancer effect. We discovered that inhibiting the expression of HMGA2 using siRNA in UTUC cells, such as BFTC909, significantly reduces cell proliferation and migration. Moreover, the addition of an HMGA2 inhibitor known as suramin enhances cytotoxic effects and decreases cell migration. Our preliminary findings provide evidence indicating a correlation between high levels of HMGA2 expression and aggressive tumor architecture in UTUC. We designed UTUC patient-derived organoids (PDO). The test results revealed that the organoids, as indicated by HE stain and Ki67 immunohistochemical (IHC) staining, closely resembled their corresponding parental tumors. Currently, it appears that the organoids have retained the original tumor structure and protein molecular expression characteristics. The PDO model is hoped to serve as a valuable tool in aiding the selection of suitable therapeutic strategies as clinical applications. This study was funded by the Chang Gung Medical Foundation, Taiwan (CMRPG8M0131, and CMRPG8M0132) and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-182A-140). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The prognostic impact of lymphovascular invasion for upper urinary tract urothelial carcinoma: A propensity score-weighted analysis.

Lymphovascular invasion (LVI) predicts poor survival in patients with pathologically localized or locally advanced upper urinary tract urothelial carcinoma (UT-UC). However, LVI is associated with high tumor grade, tumor necrosis, advanced tumor stage, tumor location, concomitant carcinoma in situ, lymph node metastasis, and sessile tumor architecture. These factors might interfere with the analysis of the impact of LVI on oncological prognosis. To address this, this study aimed to clarify the relationship between LVI and patient prognosis in UT-UC using propensity score weighting. Data were collected from 789 patients with UT-UC treated with radical nephroureterectomy without chemotherapy. We evaluated the significance of LVI in predicting metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) using propensity score weighting. All weighted baseline characteristics included in the propensity score model were balanced between the LVI (+) and LVI (-) groups. The MFS, CSS, and OS were all significantly poorer in the LVI (+) group. For patients without LVI, the 5-year MFS, CSS, and OS rates were 65.3%, 73.1%, and 67.3%, respectively, whereas the corresponding rates were 50.2%, 63.8 %, and 54.6%, respectively, for patients with LVI. (all P < .001). For patients without LVI, the 10-year MFS, CSS, and OS rates were 61.5%, 69.6%, and 59.2%, respectively, whereas those for patients with LVI were 44.5%, 57.0%, and 42.7%, respectively (all P < .001). LVI is an important pathological feature that predicts metastasis development and worse survival outcome after radical surgery in UT-UC patients.

MP48-20 COMPARING AND VALIDATING DIFFERENT NOMOGRAMS FOR PREDICTING SURVIVAL AFTER RADICAL NEPHROURETERECTOMY FOR PRIMARY UPPER URINARY TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP48)1 Sep 2021MP48-20 COMPARING AND VALIDATING DIFFERENT NOMOGRAMS FOR PREDICTING SURVIVAL AFTER RADICAL NEPHROURETERECTOMY FOR PRIMARY UPPER URINARY TRACT UROTHELIAL CARCINOMA Shicong Lai, Pengjie Wu, Jianyong Liu, Ming Liu, and Jian-Ye Wang Shicong LaiShicong Lai More articles by this author , Pengjie WuPengjie Wu More articles by this author , Jianyong LiuJianyong Liu More articles by this author , Ming LiuMing Liu More articles by this author , and Jian-Ye WangJian-Ye Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002074.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Upper urinary tract urothelial carcinoma (UTUC) is an aggressive malignancy with high risk of cancer-specific mortality. Therefore, assessing a patient’s condition and providing an accurate prognosis is crucial. Currently, several nomograms for cancer-specific survival (CSS) following RNU have been proposed. However, these nomograms incorporate different variables and only one has been externally validated. Thus, current study was designed to compare the predictive performances of these four prognostic models. METHODS: Clinicopathological and survival data from 258 primary UTUC patients who underwent RNU with bladder cuff excision between January 2004 and May 2020 were collated. Cox’s univariate and multivariable regression analyses were performed to identify independent risk factors associated with CSS. Detailed prognostic scores for every patient were calculated using regression coefficients generated with each nomogram. Performance characteristics for each nomogram were then quantified through calibration and discrimination. The nomograms were compared and contrasted using areas under curves (AUC) in the receiver operating characteristic (ROC) curve. RESULTS: Of the initial 258 patients, 115 meet our eligibility criteria. At a median follow-up of 91.7 months, 21 (18.3%) died as a consequence of UTUC. Multivariable analysis revealed that high tumor stage, positive nodal status and sessile tumor architecture were independent prognostic factors for CSS. When applied to our sample, median Cha, Rouprêt, Seisen and Yates scores were 106.2, 119.4, 197.3 and 147.8, respectively. AUCs used for predicting CSS, highlighted good predictive capabilities with 0.832, 0.833, 0.840 and 0.855, respectively. Contrasting performances suggests there is no significant difference between these nomograms (all p>0.05). Calibration plots also revealed CSS predictions at 5 years had relative concordance; however, decision curve analyses suggests the Yates nomogram holds the greatest net benefit for most of the examined 5-year CSS probabilities. CONCLUSIONS: The four nomograms studied appear accurate at predicting 5-year CSS after RNU for primary UTUC across a mainland Chinese population. This study also suggests that the Yates nomogram may be superior when calibration and decision curve analysis are taken as benchmarks. However, further external validation is still required across larger, more ethnically diverse populations before adopting this nomogram into clinical practice. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e873-e873 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shicong Lai More articles by this author Pengjie Wu More articles by this author Jianyong Liu More articles by this author Ming Liu More articles by this author Jian-Ye Wang More articles by this author Expand All Advertisement Loading ...

The Prognostic Impact of Tumor Architecture for Upper Urinary Tract Urothelial Carcinoma: A Propensity Score-Weighted Analysis.

PurposeTo assess the association of tumor architecture with cancer recurrence, metastasis, and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC) in Taiwan.Materials and MethodsData were collected from 857 patients treated with RNU between January 2005 and August 2016 in our hospital. Pathologic slides were reviewed by genitourinary pathologists. Propensity score weighting was performed for data analysis.ResultsSessile growth pattern was observed in 212 patients (24.7%). Tumor architecture exhibited a significant association with bladder cancer history, chronic kidney disease (CKD), tumor stage, lymph node status, histological grade, lymphovascular invasion, concomitant carcinoma in situ, and the variant type [standardized mean difference (SMD) > 0.1 for all variables before weighting]. In the propensity score analysis, 424 papillary and sessile tumor architecture were analyzed to balance the baseline characteristics between the groups. Tumor architecture was an independent predictor of metastatic disease and CSS (p = 0.033 and p = 0.002, respectively). However, the associations of tumor architecture with bladder and contralateral recurrence were nonsignificant (p = 0.956 and p = 0.844, respectively).ConclusionsTumor architecture of UTUC after RNU is associated with established features of aggressive disease and predictors of metastasis and CSS. Assessment of tumor architecture may help identify patients who could benefit from close follow-up or early administration of systemic therapy after RNU. Tumor architecture should be included in UTUC staging after further confirmation.

The prognostic value of tumor architecture in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy: A systematic review and meta-analysis.

There is a lack of consensus regarding the prognostic value of tumor architecture (sessile vs. papillary) in upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). The aim of the present study was to analyze the current evidence regarding the prognostic role of tumor architecture in patients undergoing RNU for UTUC through a systematic review and meta-analysis. According to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a literature search in PubMed, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases was performed for citations published prior to February 2020. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were conducted for the survival outcomes by Stata 12.0 software. We retrieved 17 studies (including 8,146 patients) evaluating the effect of tumor architecture on oncologic outcomes in patients treated with RNU. According to our final results, sessile tumor architecture had a significant correlation with worse cancer-specific survival (CSS) (HR = 1.43, 95% CI: 1.31-1.55, P < .001), overall survival (OS) (HR = 1.40, 95% CI: 1.24-1.58, P < .001), recurrence-free survival (RFS) (HR = 1.43, 95% CI: 1.35-1.53, P < .001), and progression-free survival (PFS) (HR = 1.27, 95% CI: 1.11-1.45, P = 0.001). The funnel plot test indicated that there was no significant publication bias in the meta-analysis. Besides, the findings of this study were found to be reliable by our sensitivity and subgroup analysis. Sessile tumor architecture correlates with a significantly worse survival outcome compared with papillary tumor architecture, and it can be used as a valuable biomarker for monitoring prognoses of UTUC patients.

MP82-04 THE COPY NUMBER VARIATION SIGNATURES IN UPPER TRACT UROTHELIAL CARCINOMA DEFINE DISTINCT SUBTYPES WITH PROGNOSTIC RELEVANCE

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP82)1 Apr 2020MP82-04 THE COPY NUMBER VARIATION SIGNATURES IN UPPER TRACT UROTHELIAL CARCINOMA DEFINE DISTINCT SUBTYPES WITH PROGNOSTIC RELEVANCE Bao Guan, Huan Lu, Yuan Liang, Yanqing Gong, Shiming He, Qun He, Xuesong Li, Liqun Zhou*, and Weimin Ci Bao GuanBao Guan More articles by this author , Huan LuHuan Lu More articles by this author , Yuan LiangYuan Liang More articles by this author , Yanqing GongYanqing Gong More articles by this author , Shiming HeShiming He More articles by this author , Qun HeQun He More articles by this author , Xuesong LiXuesong Li More articles by this author , Liqun Zhou*Liqun Zhou* More articles by this author , and Weimin CiWeimin Ci More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000974.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To conduct an integrated analysis of copy-number signatures and identify its prognostic value in Upper tract urothelial carcinoma (UTUC). METHODS: We performed WGS in 90 UTUC primary tumor samples, and the preoperative urine cell-free DNA from 94 patients with urothelial carcinoma (26 UTUCs; 68 bladder cancers) were analyzed by shallow whole genome sequencing(WGS). Non-negative matrix factorization (NMF) was applied to resolve CNV signatures. Next we halved this cohort in terms of the median signature contribution, and outcomes of this classification were analyzed. An independent cohort from The Cancer Genome Atlas (TCGA) bladder cancer was also bisected around the median correlation between tumor CNV component and a CNV signature component, then the outcomes analysis were conducted. Association with survival was evaluated using Kaplan-Meier and multivariable Cox regression methods. All statistical tests were two-sided. RESULTS: This 90 UTUC cohort defined Six copy number signatures (Signature1-6). Cohort patients was classified to six groups (Sig1-6) according to copy number signature’s maximum contribution. Signature6 was correlated with SNV signature 3 and 11. Besides, mutational frequency of Sig6 in BER, NER and HR pathway is much higher than the other groups. Kaplan-Meier curves showed that Sig6 has a favorable outcome. Based on the ratio of CNV in genome and contribution of signature 6 in 90 UTUC patients, this cohort can be classified into three subgroups: 1) wGIIlow, which did not exhibit a dominant copy number variation whose wGII were less than 0.1, showed significantly higher number of age-related mutational signature 1 and was associated with positive lymph node, lower percentage of CD3+ lymphocyte and stromal TIMC; 2) sig6low, which possessed lower proportion of signature 6, is significantly relavant with Sessile tumor architecture; and 3) sig6high subgroup, which exhibited higher proportion of signature 6, showed higher ratio of microsatellite instability sites. Kaplan-Meier plots revealed that the sig6high subgroup exhibited favourable outcomes compared with the sig6low and wGII-low subgroup. In muscle-invasive UTUC patients, the sig6high subgroup also exhibited best outcomes, the wGIIlow subgroup shown the worst outcomes. In multivariate Cox regression proportional analyses adjusted for the effects of clinicopathologic variables, the contribution of sig6 were still an independent prognostic factor for CSS and MFS. we verified the predictive value of signature 6 in the TCGA bladder cohort, the sig6high group in the TCGA UCB cohort also show better overall survival and metastasis-free survival. CONCLUSIONS: A novel CNV signature maybe be a promising predictive biomarker for UTUC patients in future prospective clinical trials. Source of Funding: We thank Gengyan Xiong and Lei Zhang for scientific inputs about the manuscript as well as Han Hao, Qin Tang and Xiaoteng Yu for assistance with clinicopathological characterizations. This work was supported by CAS Strategic Priority Research Program (XDA16010102 to W.C.), the National Key R&D Program of China (2018YFC2000100 to W.C.), CAS (QYZDB-SSW-SMC039 to W.C.), the National Natural Science Foundation of China (7152146 to X.L., 81672541 to W.C. and 81672546 to L.Z.), K.C. Wong Education Foundation to W.C., the Clinical Features Research of Capital (Z151100004015173 to L.Z.), the Capital Health Research and Development of Special (2016-1-4077 to L.Z.). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1246-e1247 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bao Guan More articles by this author Huan Lu More articles by this author Yuan Liang More articles by this author Yanqing Gong More articles by this author Shiming He More articles by this author Qun He More articles by this author Xuesong Li More articles by this author Liqun Zhou* More articles by this author Weimin Ci More articles by this author Expand All Advertisement PDF downloadLoading ...

Aristolochic acid containing herbs induce gender-related oncological differences in upper tract urothelial carcinoma patients.

BackgroundIn China, upper tract urothelial carcinoma (UTUC) is less prevalent but more malignant in males. This study investigates the prognostic factors and causes of gender-based differences in Chinese populations.MethodsBetween 1999 and 2011, 687 UTUC patients who underwent surgery were utilized for this study. We evaluated the differences in oncological characteristics, epigenetic biomarkers, cancer-specific survival (CSS), bladder recurrence (BR) rate, and contralateral upper tract recurrence (CUTR) rate. Smoking history, benzene exposure history, and the history of using aristolochic acid (AA) containing herbs were analyzed in detail.ResultsCompared with male patients, female patients showed poorer renal function, lower proportions of tumor stage III/IV, and smaller tumor diameters. The CSS in male patients was lower than that in female patients. Significant gender-related differences were observed concerning various prognostic factors. In female patients, poorer survival rates were attributed to the primary tumor location in the ureter, large diameter primary tumors, severe chronic kidney disease, papillary tumor architecture, high tumor stages, positive N status, and methylated ABCC6 promoters. In male patients, older age, ipsilateral hydronephrosis, large tumor diameters, sessile tumor architecture, high tumor stages, and methylated TMEFF2 promoters were associated with higher cancer-specific mortality. AA might be the main cause of these gender-based differences. The AA-induced UTUC patients presented smaller tumor diameters, lower tumor stages, fewer positive N statuses, more multifocal tumors, lower methylation indices, and poorer renal function. Although AA-induced UTUC patients exhibited better survival rates, BR and CUTR rates were significantly worse.ConclusionIn China, there exist significant AA-induced differences between male and female UTUC patients. The bladders and contralateral upper urinary tracts of AA-induced UTUC patients should be carefully monitored after surgery.

The effect of AB0 and Rhesus blood grouping systems on oncological outcome in patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma

ObjectivesTo investigate the effect of AB0 and Rhesus factor expression blood group systems on outcomes of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. Patients and methodsWe analyzed data from 271 patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy at 3 German academic institutions. Cox and logistic regression models assessed the association of AB0 blood group antigen and Rhesus factor expression with tumor biologic features and outcomes, respectively. ResultsIn total, 119 patients (43.9%) had blood group antigen A0, 42 patients (15.4%) antigen B0, 15 patients (5.5%) antigen AB, and 95 patients (35.0%) the antigen 00. A total of 231 patients (85.2%) were Rhesus factor positive. The AB0 blood group antigen expression was associated with a higher tumor grade (P = 0.049) and sessile tumor architecture (P = 0.019). Both, AB0 blood group system and Rhesus factor expression, were associated with worse performance status (P = 0.024, and P = 0.003, respectively). In contrast, Rhesus factor expression status was not associated with any clinicopathologic characteristics. Neither the AB0 blood group antigens nor the Rhesus factor was associated with survival. ConclusionAB0 blood group antigens and Rhesus factor expression are not associated with survival. The association of the AB0 blood group antigens with adverse pathological features warrants further validation.

Impact of tumor architecture on disease recurrence and cancer-specific mortality of upper tract urothelial carcinoma treated with radical nephroureterectomy.

Upper tract urinary carcinoma (UTUC) is a relatively uncommon but aggressive disease. Recent publications have assessed the prognostic significance of tumor architecture in UTUC, but there is still controversy regarding the significance and importance of tumor architecture on disease recurrence. We retrospectively reviewed the medical records of 101 patients with clinical UTUC who had undergone surgery. Univariate and multivariate analyses were conducted to identify factors associated with disease recurrence and cancer-specific mortality. As our single center study and the limited sample size may influence the clinical significance, we further quantitatively combined the results with those of existing published literature through a meta-analysis compiled from searching several databases. At a median follow-up of 41.3 months, 25 patients experienced disease recurrence. Spearman's correlation analysis showed that tumor architecture was found to be positively correlated with the tumor location and the histological grade. Kaplan-Meier curves showed that patients with sessile tumor architecture had significantly poor recurrence free survival (RFS) and cancer specific survival (CSS). Furthermore, multivariate analysis suggested that tumor architecture was independent prognostic factors for RFS (Hazard ratio, HR = 2.648) and CSS (HR = 2.072) in UTUC patients. A meta-analysis of investigating tumor architecture and its effects on UTUC prognosis was conducted. After searching PubMed, Medline, Embase, Cochrane Library and Scopus databases, 17 articles met the eligibility criteria for this analysis. The eligible studies included a total of 14,368 patients and combined results showed that sessile tumor architecture was associated with both disease recurrence with a pooled HR estimate of 1.454 and cancer-specific mortality with a pooled HR estimate of 1.416. Tumor architecture is an independent predictor for disease recurrence after radical nephroureterectomy for UTUC. Therefore, closer surveillance is necessary, especially in patients with sessile tumor architecture.

Promising role of preoperative neutrophil-to-lymphocyte ratio in patients treated with radical nephroureterectomy

ObjectiveSeveral retrospective studies with small cohorts reported neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU). We aimed at validating the predictive and prognostic role of NLR in a large multi-institutional cohort.MethodsPreoperative NLR was assessed in a multi-institutional cohort of 2477 patients with UTUC treated with RNU. Altered NLR was defined by a ratio >2.7. Logistic regression analyses were performed to assess the association between NLR and lymph node metastasis, muscle-invasive and non-organ-confined disease. The association of altered NLR with recurrence-free survival (RFS) and cancer-specific survival (CSS) was evaluated using Cox proportional hazards regression models.ResultsAltered NLR was observed in 1428 (62.8 %) patients and associated with more advanced pathological tumor stage, lymph node metastasis, lymphovascular invasion, tumor necrosis and sessile tumor architecture. In a preoperative model that included age, gender, tumor location and architecture, NLR was an independent predictive factor for the presence of lymph node metastasis, muscle-invasive and non-organ-confined disease (p < 0.001). Within a median follow-up of 40 months (IQR 20–76 months), 548 (24.1 %) patients experienced disease recurrence and 453 patients (19.9 %) died from their cancer. Compared to patients with normal NLR, those with altered NLR had worse RFS (0.003) and CSS (p = 0.002). In multivariable analyses that adjusted for the effects of standard clinicopathologic features, altered NLR did not retain an independent value. In the subgroup of patients treated with lymphadenectomy in addition to RNU, NLR was independently associated with CSS (p = 0.03).ConclusionIn UTUC, preoperative NLR is associated with adverse clinicopathologic features and independently predicts features of biologically and clinically aggressive UTUC such as lymph node metastasis, muscle-invasive or non-organ-confined status. NLR may help better risk stratify patients with regard to lymphadenectomy and conservative therapy.

The prognostic impact of squamous and glandular differentiation for upper tract urothelial carcinoma patients after radical nephroureterectomy.

To evaluate the association between tumor squamous and/or glandular differentiation and tumor biological characteristics and to validate the impact of these histologic variants on oncologic outcomes of UTUC patients. We retrospectively analyzed the data of 687 UTUC patients who underwent radical nephroureterectomy in our institute, from Aug 1, 1999, to Dec 31, 2011. All pathologic sections were reevaluated for histologic differentiation variations (squamous and glandular). The clinicopathological variables of patients were reviewed. Among the 687 UTUC patients in our study, 53 (7.7%) had squamous differentiation, 20 (2.9%) had glandular differentiation and 8 (1.2%) had both histologic variants. Patients with mixed histologic variant tended to have significant larger percentage of sessile tumor architecture (58.0 vs 18.2%), presence of CIS (7.4 vs 2.3%), advanced T stage, advanced tumor grade and lymph node metastasis (17.3 vs 6.6%; all p<0.05). Patients with squamous and/or glandular differentiation had significant worse cancer-specific survival than pure UTUC patients (p<0.001), while significant difference of recurrence-free survival between two groups was not observed (p=0.126). Patients with both squamous and glandular differentiation did not show significantly worse CSS than those with single histologic variant. Univariate analyses revealed that tumor squamous and/or glandular differentiation was a significant factor on survival (p<0.001). However, the influence did not remain significant after adjusted for other factors in the multivariate analyses (p=0.076, HR 1.42). UTUC patients with squamous and/or glandular differentiation are more likely to have aggressive tumor biological features and tend to have worse postoperative outcomes.

Predictive role of preoperative hydronephrosis on poor pathological outcomes and prognosis in upper tract urothelial carcinoma patients: Experience from a nationwide high-volume center in China.

To validate the predictive value of preoperative hydronephrosis (HN) with regard to clinicopathological outcome and prognosis in a large cohort of upper tract urothelial carcinoma (UTUC) patients, a retrospective analysis was conducted using the clinicopathological data of 520 consecutive patients treated between 2000 and 2010 at a nationwide high-volume center in China. Preoperative computed tomography or magnetic resonance imaging scans were evaluated for the presence of ipsilateral HN, and the associations between HN and pathological outcomes, patient survival and urinary tract recurrences were assessed. Ipsilateral HN was present in 271 patients (52.1%). Preoperative HN was associated with advanced age (P=0.007), sessile tumor architecture (P<0.001), ureteral location (P<0.001), higher tumor stage (P<0.001) and higher histological grade (P=0.002). Univariate and multivariate analyses revealed that poorer cancer-specific survival (CSS) and overall survival (OS) times were correlated with preoperative HN (P=0.004 and P=0.009, respectively). The 5-year CSS and OS rates for patients with HN were 86.9 and 86.2%, respectively, compared to 93.3 and 91.9% for patients without HN. For patients with muscle-invasive disease, HN remained a risk factor for poor CSS and OS (P=0.009 and P=0.012, respectively). No association was identified between HN and bladder recurrence (P=0.552) or the development of contralateral upper tract carcinoma (P=0.164). The findings indicated that preoperative HN is prevalent in UTUC. The presence of preoperative HN predicted poorer pathological outcomes and was a significant risk factor affecting survival. The evaluation of HN may be informative for decisions concerning surgical options, and the presence of HN should raise the possibility of employing an aggressive treatment approach.

Multi-institutional validation of the predictive value of Ki-67 in patients with high-grade urothelial carcinoma of the upper urinary tract.

371 Background: To validate the independent predictive value of Ki-67 in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: 475 patients from the international UTUC collaboration who underwent extirpative surgery for high-grade UTUC were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray (TMA) formed from this patient cohort. Ki-67 expression was assessed in a semi-quantitative fashion and considered overexpressed at a cut-off of 20%. Multivariate analyses (MVA) were performed to assess independent predictors of oncological outcomes and Harrell’s C indices (HCI) were calculated for predictive models. Results: Median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was overexpressed in 25.9% of patients. Ki-67 overexpression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ (CIS), and regional lymph node metastases. In Kaplan-Meier analyses, overexpressed Ki-67 was associated with worse recurrence-free (RFS) (HR 12.6, p&lt;0.001) and cancer-specific survival (CSS) (HR 15.8, p&lt;0.001). In MVA, Ki-67 was an independent predictor of RFS (HR 1.6, 95% CI 1.07-2.30, p=0.021) and CSS (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved HCI from 0.66 to 0.70 (p&lt;0.0001) for both RFS and CSS in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for RFS and 0.81 to 0.83 (p=0.005) for CSS in our post-operative model. Conclusions: Ki-67 was validated as an independent prognostic predictor of RFS and CSS in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort.

Multi-institutional Validation of the Predictive Value of Ki-67 in Patients with High Grade Urothelial Carcinoma of the Upper Urinary Tract

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, p <0.001) and cancer specific survival (HR 15.8, p <0.001). 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 (p <0.0001) 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.

Impact of Preoperative Anemia on Oncologic Outcomes of Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

We evaluated the impact of preoperative anemia on oncologic outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. A total of 282 patients with upper tract urothelial carcinoma underwent radical nephroureterectomy. Preoperatively measured hemoglobin values were stratified into normal and anemia based on the WHO classification of 13 gm/dl or less and 12 or less considered anemia in males and females, respectively. We performed sensitivity analysis based on contemporary anemia classifications adjusted for the impact of age, gender and race with anemia considered a hemoglobin value of 13.7 gm/dl or less and 13.2 or less in white males younger than 60 and 60 years old or older, respectively, and 12.2 gm/dl or less in white females of all ages. Univariable and multivariable Cox regression analyses were done to assess the effects of anemia on oncologic outcomes. Median preoperative hemoglobin was 13.2 gm/dl (IQR 11.7, 14.3). A total of 112 patients (39.7%) were anemic by the WHO classification vs 129 (45.7%) by the contemporary classification. Anemia was associated with lymph node metastasis, lymphovascular invasion, sessile tumor architecture, tumor necrosis, advanced age and a higher ECOG (Eastern Cooperative Oncology Group) performance score using the WHO and/or the contemporary definition (p ≤0.044). At a median 30-month followup anemia was associated with decreased recurrence-free (p ≤0.008) and cancer specific (p <0.001) survival on Kaplan-Meier analyses. On multivariable analysis adjusted for standard clinicopathological factors anemia remained an independent predictor of disease recurrence (HR 1.76, 95% CI 1.17-2.63 and 1.89, 95% CI 1.26-2.86) and cancer specific mortality (HR 1.88, 95% CI 1.15-3.08 and 2.04, 95% CI 1.21-3.45) by the WHO and contemporary classifications, respectively. Preoperative anemia is an independent predictor of disease recurrence and cancer specific mortality. It is associated with aggressive tumor features in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. Hemoglobin is a promising marker for patient counseling and risk stratification for additional treatment decision making.

Survival outcomes in patients undergoing neoadjuvant chemotherapy for upper tract urothelial cell carcinoma.

311 Background: High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged at surgery and has uniformly poor survival rates. Neoadjuvant chemotherapy (NAC) may provide an avenue to improve clinical outcomes in these patients prior to loss of renal function after nephroureterectomy. Methods: We performed a retrospective review of patients with high risk UTUC who received NAC followed by surgical extirpation from 2004 to 2008, a time period during which NAC was uniformly offered to patients. The study group was then compared to a historical cohort of similar risk patients who underwent initial surgical treatment from 1993-2004. Results: Of the 120 patients, 31 patients with high-risk cN0 disease received NAC, 76 had initial surgery, and 13 had surgical consolidation of clinically involved lymph nodes after chemotherapy. Those receiving NAC had an improved OS and DSS (p=0.018 and p=0.0005, respectively). The 3 and 5 year DSS for cN0 patients receiving NAC was 90% and 90% (OS 87% and 80% respectively) with median follow up of 64 months. The 3 and 5 year DSS and OS for the historical group was 70% and 62%, with median follow up of 87 months. The two groups had similar demographics and clinical features, except for a higher proportion of sessile tumor architecture in the NAC group (p=0.021). Full dose cisplatin or high dose ifosfamide based chemotherapy was given to 22 (71%) patients, while 4 (13%) received a modified dose of cisplatin, and 5 (16%) received a nephron sparing combination. Pathologic downstaging to &lt;=pT1N0 was significantly associated with NAC (65% vs 26% initial, p=0.004). The 13 patients with node positive disease at presentation received NAC followed by surgical consolidation with median OS 78 months. The 3 and 5 year DSS was 77% and 67% (OS 69% and 60% respectively). Conclusions: Neoadjuvant chemotherapy improves survival in patients with UTUC compared with historical expectations. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy especially considering the limitations of administering curative cisplatin-based chemotherapy after nephrectomy.

Impact of Histological Variants on Clinical Outcomes of Patients with Upper Urinary Tract Urothelial Carcinoma

We investigated the clinical and prognostic impact of variant histologies on upper tract urothelial carcinoma outcomes after radical nephroureterectomy. Data on 1,648 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy without preoperative chemotherapy or radiotherapy were reviewed for histological differentiation and variants. We analyzed differences between pure upper tract urothelial carcinoma and upper tract urothelial carcinoma with variant histology, and differences in the histological variants using different stratifications. A total of 398 patients (24.2%) had histological upper tract urothelial carcinoma variants. The most common variants were squamous cell and glandular differentiation in 9.9% and 4.4% of cases, respectively. Histological variants were associated with advanced tumor stage, tumor multifocality, sessile tumor architecture, tumor necrosis, lymphovascular invasion and lymph node metastasis compared to pure upper tract urothelial carcinoma (p ≤0.031). On univariable analysis variant histology was associated with disease recurrence (p = 0.002) and cancer specific mortality (p = 0.003). In 174 patients treated with adjuvant chemotherapy there was no difference in disease recurrence or survival between variant histology and pure upper tract urothelial carcinoma (p = 0.42 and 0.59, respectively). On multivariable analysis adjusted for the effects of standard clinicopathological characteristics variant histology was not associated with either end point. Almost 25% of patients with upper tract urothelial carcinoma treated with radical nephroureterectomy harbored histological variants. Variant histology was associated with features of biologically aggressive upper tract urothelial carcinoma. While variant histology is associated with worse outcomes on univariable analysis but this effect did not remain significant on multivariable analysis.

Predicting clinical outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.

267 Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. Methods: Our study included 2,244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant CIS. The cohort was split for development (12 centers, n=1273) and external validation (11 centers, n=971). Results: At a median follow-up of 45 months, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p-for-trend &lt;0.001), lymph node metastasis (HR:1.98, p=0.002), lymphovascular invasion (HR:1.66, p&lt;0.001), sessile tumor architecture (HR:1.76, p&lt;0.001), and concomitant CIS (HR:1.33, p=0.035) were associated with disease recurrence. Similarly, T classification (p-for-trend &lt;0.001), lymph node metastasis (HR:2.23, p=0.001), lymphovascular invasion (HR:1.81, p&lt;0.001), and sessile tumor architecture (HR:1.72, p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be utilized for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

Predicting Clinical Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

BackgroundNovel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. ObjectiveWe tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. Design, setting, and participantsOur study included 2244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant carcinoma in situ (CIS). The cohort was randomly split for development (12 centers, n=1273) and external validation (11 centers, n=971). InterventionsAll patients underwent RNU. MeasurementsUnivariable and multivariable models addressed RFS, CSS, and comparison of discrimination and calibration with American Joint Committee on Cancer (AJCC) stage grouping. Results and limitationsAt a median follow-up of 45 mo, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p for trend <0.001), lymph node metastasis (hazard ratio [HR]: 1.98; p=0.002), lymphovascular invasion (HR: 1.66; p<0.001), sessile tumor architecture (HR: 1.76; p<0.001), and concomitant CIS (HR: 1.33; p=0.035) were associated with disease recurrence. Similarly, T classification (p for trend<0.001), lymph node metastasis (HR: 2.23; p=0.001), lymphovascular invasion (HR: 1.81; p<0.001), and sessile tumor architecture (HR: 1.72; p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. ConclusionsUsing standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be used for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

The Impact of Tumor Multifocality on Outcomes in Patients Treated With Radical Nephroureterectomy

Background The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood. Objective To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU). Design, setting, and participants The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter. Intervention All patients were treated with either open or laparoscopic RNU. Measurements Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality. Results and limitations Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0–101). Tumor multifocality was significantly associated with a history of previous BCa ( p = 0.032), lymph node involvement ( p = 0.036), tumor location in the ureter ( p = 0.003), higher tumor stage ( p < 0.001), higher tumor grade ( p < 0.001), sessile tumor architecture ( p = 0.003), and LVI ( p = 0.001). In organ-confined patients, tumor multifocality was an independent predictor of both disease progression (hazard ratio [HR]: 1.43; p = 0.019) and cancer-specific mortality (HR: 1.46; p = 0.027). When assessed in all patients, tumor multifocality was associated with both disease progression and cancer-specific mortality in univariable ( p = 0.005 and p = 0.006, respectively) but not in multivariable analyses ( p = 0.468 and p = 0.798, respectively). The main limitation is the retrospective design of the study. Conclusions Tumor multifocality is an independent prognosticator of disease progression and cancer-specific mortality in patients with organ-confined UTUC treated with RNU. Multifocal organ-confined patients with UTUC may need closer follow-up. Integration of tumor multifocality with other factors may help identify those patients who would benefit from multimodal therapy.