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.     

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.     

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).

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.     

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。     

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.     

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.     

Therapeutic strategies for upper tract urothelial carcinoma

Introduction: Many controversies exist regarding the appropriate management of patients with upper tract urothelial carcinoma (UTUC), including staging, surgical management, use of systemic therapy, and prevention of bladder recurrence. Due to the rarity of this condition, high-level evidence is often lacking and in many cases guidelines are extrapolated from existing evidence on urothelial bladder cancer.

Areas covered: This review paper summarizes the evidence on proper diagnosis and staging, surgical techniques, prevention of bladder recurrences, the use of local or systemic treatments in both neoadjuvant and adjuvant settings as well as special consideration for hereditary UTUC.

Expert commentary: UTUC is a rare malignancy and slow progress is being made in the acquisition of high-quality evidence in this field. Treatments that facilitate preservation of the kidney are being explored such as advanced endoscopic techniques or partial resection of ureteral disease with seemingly acceptable oncological results. Further prospective evidence is needed.     

An audit of nephroureterectomy for upper tract urothelial carcinoma

Background

The boundary of nephroureterctomy has been revisited and lymph node dissection has been recommended recently. We investigated the role of synchronous ipsilateral adrenalectomy in treating patients with upper tract urothelial carcinoma.

Methods

110 patients with clinically localized upper tract urothelial carcinoma treated by nephroureterectomy and bladder cuff resection were retrospectively evaluated. 70 patients underwent nephroureterectomy without concomitant ipsilateral adrenalectomy, whereas nephroureterectomy and ipsilateral adrenalectomy was performed in other 40 patients. Cancer specific, metastasis and local recurrence free survival during a follow-up of median 46 months were analyzed.

Results

No patient had adrenal metastasis among the 40 adrenalectomized patients. A total of 4 patients developed local recurrences; including 1 of the 70 adrenalectomy-sparing and 3 of the 40 adrenalectomized patients (p = 0.102, chi-square test). Five patients with adrenalectomy and four without adrenalectomy had distant metastases (p = 0.212, chi-square test). The five-year local recurrence free survival (p = 0.09, log-rank test), metastasis-free survival (p = 0.292, log-rank test), and cancer-specific survival (p = 0.117, log-rank test) did not have significant difference between both groups.

Conclusions

This is the only study in recent 2 decades to evaluate the necessity of synchronous adrenalectomy in treating localized upper tract urothelial carcinoma. Adrenal-sparing nephroureterectomy seems justified for clinically localized upper tract urothelial carcinoma.     

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.     

不同预防性膀胱内化疗方案对上尿路尿路上皮癌肾输尿管切除术后膀胱癌复发的影响

目的:比较不同预防性膀胱灌注化疗方案对UTUC患者的OS、CSS、IVRFS的影响。方法:回顾性分析2010年至2020年在我院泌尿外科接受RNU手术的387例UTUC患者的临床病例资料。术后随访10年,观察生存情况,同时对于患者的临床病理相关性数据进行统计学分析,选择Log-rank检验和Kaplan-Meier法,单因素多因素生存分析选择Cox回归分析。结果:所有患者的中位年龄为67岁［四分位数范围(IQR):33~90岁］,所有患者的中位随访时间为44个月［四分位数范围(IQR):3~140月］。三组患者的基线资料方面没有显著差异。Kaplan-Meier曲线显示,灌注组与未灌注组间,未灌注组、单次灌注组、多次灌注组三组间的总体生存率(OS)均有显著差异(P<0.000 1),三组间的肿瘤特异性存活率(CSS)有显著差异(P<0.000 1),同样三组间的膀胱内无复发生存率(IVRFS)也有显著差异(P=0.005)。未灌注组、单次灌注组与多次灌注组三组患者的1年,3年和5年的OS分别为85.3%、70.2%和61% vs 96.1%、84.1%和73.5% vs 96.8%、88.5%和84.3%。三组患者的1年,3年和5年的CSS分别为86.6%、73.6%和66.6% vs 97.4%、85.2%和74.4% vs 97.8%、89.4%和87%。三组患者的1年,3年和5年的IVRFS分别为95.2%、86.7%和74.1% vs 98.5%、89.4%和81.1% vs 98.9%、94.7%和88%。结论:术后膀胱内化疗可以明显降低UTUC患者的膀胱内复发率,尤其是侵袭性或高度恶性的UTUC。此外,我们认为多次膀胱灌注的疗效可能优于单次灌注。     

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.     

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.     

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.     

Endoscopic management of upper tract urothelial carcinoma: Improved prediction of invasive cancer using a ureteroscopic scoring model

Background

The aim of this study was to investigate clinical and ureteroscopic factors considered as important for the prediction of invasive upper tract urothelial carcinoma (UTUC) and establish a model using a new ureteroscopic scoring.

Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy

BACKGROUND:

The prevalence of chronic kidney disease (CKD) in patients with upper tract urothelial carcinoma (UTUC) is poorly defined, both before and after nephrouretectomy. Although multimodal treatment paradigms for UTUC are under‐developed, this has important implications on patients' ability to receive cisplatin‐based combination chemotherapy (CBCC).

METHODS:

Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula in 336 patients with UTUC, who were treated at the Cleveland Clinic by nephroureterectomy since 1992. An eGFR cutoff of 60 mL/min/1.73 m² was used to determine the presence of CKD and eligibility for CBCC.

RESULTS:

Median age was 72 years and median preoperative eGFR was 59 mL/min/1.73m². Before nephroureterectomy, only 48% of patients were eligible to receive CBCC and this decreased to 22% postoperatively (P < .001). In the 144 patients with pT2‐pT4 and/or pN1‐pN3 disease who are suitable to receive CBCC, these proportions were 40% and 24%, respectively (P = .009). Although 50 patients overall received some form of perioperative chemotherapy, only 3 and 11 patients received neoadjuvant and adjuvant CBCC, respectively.

CONCLUSIONS:

CKD is prevalent in the UTUC population and a minority of patients has an optimal eGFR to receive neoadjuvant CBCC. Nephrouretectomy may eliminate CBCC as a therapeutic option in 49% of high‐risk patients if it is deferred to the adjuvant setting. Multimodal treatment strategies for UTUC should focus on neoadjuvant chemotherapy, as few patients are eligible for adjuvant CBCC because of the substantial decline in eGFR caused by nephroureterectomy. Cancer 2010. © 2010 American Cancer Society.