External validation of an online nomogram in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma

Background:

The objective was to validate an online nomogram developed based on the French collaborative national database on upper urinary tract urothelial carcinoma (UUT-UC) using a different cohort.

Methods:

The study comprised 328 patients with UUT-UC who underwent radical nephroureterectomy. The discrimination of models was quantified using Harrell''s concordance index. The relationship between the model-derived and actuarial cancer-specific mortality was graphically explored within calibration plots. Calibration was also assessed using the quartiles of the predicted survival at 3 and 5 years and calculation of the corresponding observed Kaplan–Meier estimates. Clinical net benefit was evaluated constructing decision curve analysis.

Results:

The discrimination accuracy of the nomograms at 3 and 5 years was 71.6% and 71.8%, respectively. Although nomograms discriminated well by Kaplan–Meier curves, and log-rank tests were all highly significant, the calibration plots tended to exaggerate the overestimation of mortality between predicted and observed probabilities at 3 and 5 years for survival. When compared with the AJCC/UICC staging system, the nomograms performed well across a wide range of threshold probabilities using decision curve analysis.

Conclusion:

The online nomogram is a highly accurate prognostic tool for patients with UUT-UC treated with radical nephroureterectomy. The model can provide an accurate estimate of the individual risk of cancer-specific mortality. Further improvement and implementation of novel molecular marker is needed.     

Association of perioperative blood transfusion with oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma

BackgroundTo test the hypothesis that perioperative blood transfusion (PBT)impacts oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).MethodsRetrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU between 1987 and 2007.Cox regression models addressed the association of PBT with disease recurrence, cancer-specific mortality and any-cause mortality.ResultsA total of 510 patients (20.5%) patients received PBT. Within a median follow-up of 36 months (Interquartile range: 55 months), 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Patients who received PBT were at significantly higher risk of disease recurrence, cancer-specific mortality and overall mortality than patients not receiving PBT in univariable Cox regression analyses. In multivariable Cox regression analyses that adjusted for the effects of standard clinicopathologic features, PBT did not remain associated with disease recurrence (HR: 1.11; 95% CI 0.92–1.33, p = 0.25), cancer-specific mortality (HR: 1.09; 95% CI 0.89–1.33, p = 0.41) or overall mortality (HR: 1.09; 95% CI 0.93–1.28, p = 0.29).ConclusionsIn patients undergoing RNU for UTUC, PBT is associated with disease recurrence, cancer-specific survival or overall survival in univariable, but not in multivariable Cox regression analyses.     

Prognostic relevance of postoperative platelet count in upper tract urothelial carcinoma after radical nephroureterectomy

Aim of the studyTo assess the impact of perioperative platelet count (PLT) kinetics on recurrence-free survival (RFS) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).MethodsFrom three prospectively maintained databases of three tertiary care centres a total of 269 patients undergoing RNU without perioperative treatment between 1996 and 2011 were considered for this analysis. Pre- and postoperatively elevated PLT count was defined as >400 × 10⁹/L. PLT levels were measured 1–3 days preoperatively and 7–10 days postoperatively. The median follow-up was 24 months (Interquartile range (IQR): 10–52). A new weighted scoring model was developed to predict recurrence after RNU based on significant parameters of multivariable analysis.ResultsThe 5-year RFS in patients with preoperatively normal and elevated PLT count was 58.3% and 29.3%, respectively (p < 0.001). The 5-year-RFS was 57.6% in patients with normal postoperative PLT count and 29.7% in those with elevated PLT levels (p < 0.001). In multivariable analysis, pT-stage, lymphovascular invasion, ureteral margin status and postoperative thrombocytosis remained independent predictors for RFS. The 5-year RFS in patients with a score of 0 (low-risk), 1 (intermediate-risk) and 2–4 (high-risk) was 77.7%, 47.5% and 12.3%, respectively (p < 0.001). Consideration of the variable postoperative thrombocytosis in the final model increased its predictive accuracy by 1.9% with a concordance index of 0.758 (p = 0.015).ConclusionPLT kinetics is significantly associated with RFS after RNU for UTUC. We constructed a simple, PLT-based prognostic model for recurrence after RNU.     

Highly predictive survival nomogram after upper urinary tract urothelial carcinoma

BACKGROUND:

Nephroureterectomy is the surgical standard of care for patients with upper urinary‐tract urothelial carcinoma. The objectives of the current study were to identify the most informative predictors of cancer‐specific mortality after nephroureterectomy, to devise an algorithm capable of predicting the individual probability of cancer‐specific mortality, and to compare its prognostic accuracy to that of the International Union Against Cancer (UICC) staging system.

METHODS:

Within the Surveillance, Epidemiology, and End Results database, the authors identified 5918 patients who had been treated with nephroureterectomy. Within the development cohort (n = 2959), multivariate Cox regression models predicting cancer‐specific mortality were fitted by using age, stage, nodal status, sex, grade, race, type of surgery (nephroureterectomy with or without bladder‐cuff removal), and tumor location (renal pelvis vs ureter). Backward variable elimination according to the Akaike information criterion identified the most accurate and parsimonious model. Model validation and calibration were performed within the external validation cohort (n = 2959). External validation was also applied to the UICC staging system.

RESULTS:

The 5‐year freedom from cancer‐specific mortality rates in both the development and external validation cohorts was 77.3%. The most informative and parsimonious nomogram for cancer‐specific‐mortality–free survival relied on age, pT and pN stages, and tumor grade. In external validation, nomogram prediction of 5‐year cancer‐specific‐mortality–free rate was 75.4% accurate and was significantly better (P < .001) than the UICC staging system (64.8%).

CONCLUSIONS:

The current nomogram is capable of predicting the prognosis in patients with upper urinary‐tract urothelial carcinoma treated by nephroureterectomy with better accuracy than the UICC staging system. The authors recommend the application of this nomogram to routine clinical practice when counseling or making clinical decisions. Cancer 2010. © 2010 American Cancer Society.     

糖尿病对上尿路尿路上皮癌根治术后发生膀胱内肿瘤的风险分析

目的：探讨合并糖尿病（diabetes mellitus ,DM）的上尿路尿路上皮癌（upper urinary tract urothelial carcinoma ,UUT-UC）患者行根治性肾输尿管切除术（radical nephroureterectomy ,RNU ）及膀胱袖口状切除术后是否增加膀胱内肿瘤发生的风险。方法：回顾性分析天津医科大学第二医院2005年1 月至2013年12月282 例行根治性肾输尿管切除术及膀胱袖口状切除术,且既往无膀胱肿瘤病史的UUT-UC 患者临床病理资料,比较非DM组（233 例）与DM组（49例）无复发生存期（recurrence-free survival ,RFS）及肿瘤特异性生存期（cancer-specific survival ,CSS）,并分析年龄、DM、病理分级及分期等因素对患者术后膀胱内肿瘤发生的影响。结果：纳入研究的患者术后中位随访时间为41个月,282 例中80例（28.4%）发生膀胱内肿瘤,中位发生时间为11个月。非DM患者RFS 较DM患者显著延长（P = 0.013）。 Cox 回归模型多因素分析显示,DM（P = 0.014）、肾孟癌合并输尿管癌（P = 0.001）与术后化疗（P = 0.024）是术后膀胱内肿瘤发生独立影响因素。结论：DM增加UUT-UC 患者术后膀胱内肿瘤发生风险,因此需要加强对合并DM患者术后的密切随访及血糖控制。     

Robot-assisted versus open radical nephroureterectomy for urothelial carcinoma of the upper urinary tract: A retrospective cohort study across ten years

PurposeRadical nephroureterectomy is the gold standard of treatment for high-risk non-metastatic urothelial carcinoma of the upper urinary tract. However, the optimal surgical approach remains a controversial debate. This study compared the perioperative and oncological outcomes of open and robot-assisted radical nephroureterectomies.Methods131 consecutive radical nephroureterectomies (66 robot-assisted nephroureterectomies vs. 65 open nephroureterectomies) for urothelial carcinoma of the upper urinary tract at a single tertiary referral center were included from 2009 to 2019. The perioperative and oncological outcomes were compared between both surgical approaches, including logistic regression analysis, propensity score matching, Kaplan Meier analyses, and Cox regression models.ResultsOverall, robot-assisted surgery had less blood loss (150 ml vs. 250, p = 0.004) and less positive surgical margins (1.5% vs. 15.4%, p = 0.004) at a comparable operating time (robotic 188min vs. 178). Any grade complications were more frequent after open surgery (40.9% vs. 63.1%, p = 0.011), and the length of stay was shorter after robotic nephroureterectomy (9 days vs. 12, p < 0.001). These differences remained significant in the propensity score matched analysis, except for the complication rates, which were still lower for the robotic approach, but no longer significant. At a median follow-up of 30.9 months (range 1.4–129.5), neither the progression-free survival (PFS, 2-year: robotic 66.7% vs. open 55.3%), nor the overall survival differed significantly (OS, 2-year: robotic 76.2% vs. open 68.4%). In the Cox regression, the surgical approach did not impact the PFS or OS. Lymph node metastases (HR 3.32, p = 0.008) had the strongest impact on the PFS besides patient age (HR 1.51 per 10 years, p = 0.025) and prior cystectomy (HR 2.42, p = 0.026) in the multivariate analysis.ConclusionsRobot-assisted radical nephroureterectomy had significant perioperative advantages at comparable oncological outcomes compared to open surgery for the treatment of urothelial carcinoma of the upper urinary tract at a high volume center, experienced in robotic surgery.     

Contralateral upper tract urothelial carcinoma after nephroureterectomy: the predictive role of DNA methylation

Background

Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients.

Methods

In a retrospective design, methylation of 10 genes was analyzed on tumor specimens belonging to 664 consecutive patients treated by RNU for primary UTUC. Median follow-up was 48 mo (range: 3–144 mo). Gene methylation was accessed by methylation-sensitive polymerase chain reaction, and we calculated the methylation index (MI), a reflection of the extent of methylation. The log-rank test and Cox regression were used to identify the predictor of contralateral UTUC recurrence.

Results

Thirty (4.5%) patients developed a subsequent contralateral UTUC after a median follow-up time of 27.5 (range: 2–139) months. Promoter methylation for at least one gene promoter locus was present in 88.9% of UTUC. Fewer methylation and lower MI (P = 0.001) were seen in the tumors with contralateral UTUC recurrence than the tumors without contralateral recurrence. High MI (P = 0.007) was significantly correlated with poor cancer-specific survival. Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU.

Conclusions

Our data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU. Such information could help identify patients at high risk of new contralateral UTUC recurrence after RNU who need close surveillance during follow up.     

Management of upper urinary tract urothelial carcinoma

Upper urinary tract urothelial carcinoma (UTUC) is relatively uncommon. In this article, we review prognostic factors, criteria and indications for treatment with the available modalities using contemporary data. A systematic search on PubMed was performed using the keywords ‘upper tract urothelial carcinoma’, ’upper tract transitional cell carcinoma’, ’nephroureterectomy’, ‘laparoscopic’, ‘endoscopic’ and ‘prognostic factor’. The literature on UTUC is scarce. No prognostic factors have been formally validated in either the diagnosis or treatment of UTUC. The gold-standard management for invasive UTUC is radical nephroureterectomy with a bladder-cuff excision. Laparoscopic and endoscopic approaches represent alternatives in properly selected individuals. Segmental ureterectomy may also be considered. The extent and role of lymph node dissection remains to be validated. Chemotherapy may also be considered in select patients. Additional multi-institutional studies are needed to identify and validate prognostic factors that can predict the outcomes of patients diagnosed with UTUC. Randomized controlled trials are needed to assess the efficacy of the treatment modalities.     

上尿路移行细胞癌术后预防性膀胱灌注的临床研究

目的:探讨上尿路移行细胞癌术后预防性膀胱灌注的有效性。方法:61例上尿路移行细胞癌患者行根治性切除术,其中34例患者术后预防性使用吡柔比星膀胱灌注,27例患者单纯随访,比较两组患者2年内膀胱肿瘤的发生率以及发生时间,并观察药物灌注毒副反应发生的情况。结果:吡柔比星灌注组膀胱癌发生率为14.7%,观察随访组膀胱癌的发生率为37.0%,差异有统计学意义(P<0.05),再发时间分别为20个月和14个月,二者比较差异有统计学意义(P<0.05)。患者灌注过程中均耐受,未出现中止灌注的情况。结论:本研究初步显示,吡柔比星预防性膀胱灌注可有效减少膀胱肿瘤的发生,毒副反应少,值得临床推广。     

DNA copy number aberrations associated with lymphovascular invasion in upper urinary tract urothelial carcinoma

Recent studies have reported that lymphovascular invasion (LVI) is a predictor of patient prognosis in upper urinary tract urothelial carcinoma (UUTUC). DNA copy number aberrations (DCNAs) identified by array-based comparative genomic hybridization (aCGH) had not previously been examined in UUTUC. We therefore examined DCNAs in UUTUC and compared them with DCNAs in LVI. We applied aCGH technology using DNA chips spotted with 4,030 BAC clones to 32 UUTUC patients. Frequent copy number gains were detected on chromosomal regions 8p23.1 and 20q13.12, whereas frequent copy number losses were detected on chromosomal regions 13q21.1, 17p13.1, 6q16.3, and 17p11.2. DCNAs occurred more frequently in tumors with LVI than in those without it (P = 0.0002), and this parameter was more closely associated with LVI than with the tumor grade or pT stage. Disease-specific survival rate was higher in tumors without LVI than in those with it (P = 0.0120); however, tumor grade and stage were not significant prognostic factors of patient outcome. These data support our hypothesis that tumors with LVI have more genetic alterations in terms of total numbers of DCNAs than those without, and provide proof that aggressive adjuvant therapy should be considered for UUTUC patients with LVI.     

High visfatin expression predicts poor prognosis of upper tract urothelial carcinoma patients

Visfatin, a newly discovered adipocytokine, is a pro-inflammatory cytokine. This study aimed to evaluate the predictive value of visfatin on prognosis of patients with upper tract urothelial carcinoma. One-hundred and five patients (median age=64, range=24-84 years) were included in this study. Visfatin expression in upper tract urothelial carcinoma tissues was analyzed by immunohistochemistry. Visfatin expression was correlated with clinicopathologic variables using the χ² test. The prognostic value of visfatin for recurrence-free and cancer-specific survival was evaluated by Kaplan-Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Cox regression model was also used to evaluate the hazard ratios of visfatin on survival. High visfatin expression in upper tract urothelial carcinoma tissues was significantly correlated with tumor stage (P=0.001), grade (P=0.007) and p53 expression (P=0.07). High visfatin expression was associated with poor recurrence-free and cancer-specific survival. Cox regression analysis also revealed that visfatin is an independent predictor of recurrence-free (HR=3.22, P=0.009) and cancer-specific survival (HR=5.74, P=0.023). Our findings indicated that higher visfatin expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of visfatin in the carcinogenesis of upper tract urothelial carcinoma.     

Rationale and timing of perioperative chemotherapy for upper-tract urothelial carcinoma

Radical surgery alone for high-risk upper-tract urothelial carcinoma (UTUC) is often inadequate for long-term cancer control. Numerous studies implicate failure presumably attributable to metastatic disease. Therefore, multimodal therapy by way of perioperative chemotherapy is integral to improve cancer outcomes and disease-specific survival. Despite this apparent reality, there is lack of consensus regarding which patients will need additional therapy, optimal timing for delivery of agents, and specific regimens to be utilized. Progress is being made, however, to explore these issues both by extrapolation from the bladder cancer literature as well as studying outcomes from retrospective UTUC series. Prospectively accruing studies for both neoadjuvant and adjuvant chemotherapy will likely mature in the next 5 years thereby providing higher level data to better guide standard of care.     

Prolonged pneumoperitoneum time is an independent risk factor for intravesical recurrence after laparoscopic radical nephroureterectomy in upper tract urothelial carcinoma

Objective

To evaluate the impact of pneumoperitoneum time on intravesical recurrence (IVR) in upper tract urothelial carcinoma (UTUC) patients who underwent laparoscopic radical nephroureterectomy (LRNU).

上尿路尿路上皮癌淋巴结清扫的研究进展

上尿路尿路上皮癌(UTUC)指发生于肾盂及输尿管的尿路上皮恶性肿瘤,约占全部尿路上皮癌的 5%～10%。目前,UTUC淋巴引流的解剖范围暂不明确,一些研究表明淋巴结清扫范围对患者生存的影响可能大于清扫淋巴结数量的影响,但这一观点尚未得到证实。近年来,由于微创手术的快速发展,虽然在技术操作方面和标准化方面取得了重大进展,但对于淋巴结清扫的意义和范围仍缺乏共识。本文就UTUC淋巴结清扫的意义、范围、适应证、并发症及微创手术地位的研究进展作一综述。     

Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multi-institutional dataset from 3 European centers

BACKGROUND: The objective of the current study was to identify variables that were predictive of cancer-specific survival in patients with nonmetastatic transitional cell carcinoma of the upper urinary tract (UUT-TCC). METHODS: Clinical and pathologic data from 269 patients who underwent nephroureterectomy for UUT-TCC from 1989 to 2005 in 3 urologic European centers were collected retrospectively. Log-rank tests and Cox proportional-hazards regression models were used for univariate and multivariate analyses. RESULTS: Two hundred fifty patients underwent nephroureterectomy, and 19 patients underwent concomitant cystectomy for synchronous muscle-invasive bladder cancer. The median follow-up of the whole cohort was 34 months, and the median follow-up of the patients who remained alive and disease-free was 52 months. At follow-up, 57 cancer-related deaths (21.2%) were censored, and 169 patients (62.8%) were alive and disease-free. On univariate analysis, a history of previous bladder cancer, pathologic stage of the primary tumor and lymph nodes, tumor grade, the presence of lymphovascular invasion, tumor site, synchronous muscle-invasive bladder TCC, and tumor multifocality were associated with cancer-specific survival probabilities. On multivariate analysis, pathologic stage of the primary tumor and lymph nodes, tumor multifocality within the UUT, synchronous muscle-invasive bladder TCC, and a history of bladder TCC before the diagnosis of UUT-TCC were independent predictors of cancer-specific survival probabilities. CONCLUSIONS: In a multi-institutional dataset of patients who had undergone nephroureterectomy for UUT-TCC, the current results indicated that pathologic stage of the primary tumor and lymph nodes, a history of prior bladder TCC, the presence of synchronous muscle-invasive bladder cancer, and tumor multifocality within the UUT were independent predictors of cancer-specific survival probabilities.     

Cancer-specific survival after radical nephroureterectomy for upper urinary tract urothelial carcinoma: proposal and multi-institutional validation of a post-operative nomogram

Background:

Owing to the scarcity of upper urinary tract urothelial carcinoma (UUT-UC) it is often necessary for investigators to pool data. A patient-specific survival nomogram based on such data is needed to predict cancer-specific survival (CSS) post nephroureterectomy (NU). Herein, we propose and validate a nomogram to predict CSS post NU.

Patients and methods:

Twenty-one French institutions contributed data on 1120 patients treated with NU for UUT-UC. A total of 667 had full data for nomogram development. Study population was divided into the nomogram development cohort (397) and external validation cohort (270). Cox proportional hazards regression models were used for univariate and multivariate analyses and to build a nomogram. A reduced model selection was performed using a backward step-down selection process, and Harrell''s concordance index (c-index) was used for quantifying the nomogram accuracy. Internal validation was performed by bootstrapping and the reduced nomogram model was calibrated.

Results:

Of the 397 patients in the nomogram development cohort, 91 (22.9%) died during follow-up, of which 66 (72.5%) died as a consequence of UUT-UC. The actuarial CSS probability at 5 years was 0.76 (95% CI, 71.62-80.94). On multivariate analysis, T stage (P<0.0001), N status (P=0.014), grade (P=0.026), age (P=0.005) and location (P=0.022) were associated with CSS. The reduced nomogram model had an accuracy of 0.78. We propose a nomogram to predict 3 and 5-year CSS post NU for UUT-UC.

Conclusion:

We have devised and validated an accurate nomogram (78%), superior to any single clinical variable or current model, for predicting 5-year CSS post NU for UUT-UC.     

Oncologic outcomes for open and laparoscopic radical nephroureterectomy in patients with upper tract urothelial carcinoma

Background

Oncologic benefits of laparoscopic radical nephroureterectomy (LNU) are unclear. We aimed to evaluate the impact of surgical approach for radical nephroureterectomy on oncologic outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC).

Methods

Of 426 patients who underwent radical nephroureterectomy at five medical centers between February 1995 and February 2017, we retrospectively investigated oncological outcomes in 229 with locally advanced UTUC (stages cT3-4 and/or cN+). The surgical approach was classified as open nephroureterectomy (ONU) or LNU, and oncologic outcomes, including intravesical recurrence-free survival (RFS), visceral RFS, cancer-specific survival (CSS), and overall survival (OS), were compared between the groups. The inverse probability of treatment weighting (IPTW)-adjusted Cox-regression analyses was performed to evaluate the impact of LNU on the prognosis.

Results

Of the 229 patients, 48 (21%) underwent LNU. There were significant differences in patient backgrounds, including preoperative renal function, lymph-node involvement, lymphovascular invasion, and surgical margins, between the groups. Before the background adjustment, intravesical RFS, visceral RFS, CSS, and OS were significantly inferior in the ONU group than in the LNU group. However, in the IPTW-adjusted Cox-regression analysis, no significant differences were observed in intravesical RFS (hazard ratio [HR], 0.65; P = 0.476), visceral RFS (HR, 0.46; P = 0.109), CSS (HR, 0.48; P = 0.233), and OS (HR, 0.40; P = 0.147).

Conclusion

Surgical approaches were not independently associated with prognosis in patients with locally advanced UTUC.