Upper Tract Urinary Carcinoma: A Unique Immuno-Molecular Entity and a Clinical Challenge in the Current Therapeutic Scenario.

Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract, which consists of bladder cancer (BC) for 90%, while 5% to 10%, of urinary tract UC (UTUC). BC and UTUC are characterized by distinct phenotypical and genotypical features as well as specific gene- and protein- expression profiles, which result in a diverse natural history of the tumor. With respect to BC, UTUC tends to be diagnosed in a later stage and displays poorer clinical outcome. In the present review, we seek to highlight the individuality of UTUC from a biological, immunological, genetic-molecular, and clinical standpoint, also reporting the most recent evidence on UTUC treatment. In this regard, while the role of surgery in nonmetastatic UTUC is undebated, solid data on adjuvant or neoadjuvant chemotherapy are still an unmet need, not permitting a definite paradigm shift in the standard treatment. In advanced setting, evidence is mainly based on BC literature and retrospective studies and confirms platinum-based combination regimens as bedrock of first-line treatment. Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Moreover, atezolizumab performed well as a maintenance treatment, while pembrolizumab as a single agent achieved promising outcomes in second-line setting. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment.

Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma.

BACKGROUND: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). METHODS: In this cohort study we recruited 402 patients from six Hunan hospitals who underwent ureteroscopy for hematuria, including 95 patients with UTUC and 307 patients with non-UTUC findings. Midstream morning urine samples were collected before ureteroscopy and surgery. DNA was extracted and qPCR was used to analyze mutations in TERT and FGFR3 and the methylation of NRN1. In the training set, the random forest algorithm was used to build an optimal panel. Lastly, the Beijing cohort (n = 76) was used to validate the panel. RESULTS: The panel combining the methylation with mutation markers led to an AUC of 0.958 (95% CI: 0.933-0.975) with a sensitivity of 91.58% and a specificity of 94.79%. The panel presented a favorable diagnostic value for UTUC vs. other malignant tumors (AUC = 0.920) and UTUC vs. benign disease (AUC = 0.975). Furthermore, combining the panel with age revealed satisfactory results, with 93.68% sensitivity, 94.44% specificity, AUC = 0.970 and NPV = 98.6%. In the external validation process, the model showed an AUC of 0.971, a sensitivity of 95.83% and a specificity of 92.31, respectively. CONCLUSIONS: A novel diagnostic model for analyzing hematuria patients for the risk of UTUC was developed, which could lead to a reduction in the need for invasive examinations. Combining NRN1 methylation and gene mutation (FGFR3 and TERT) with age resulted in a validated accurate prediction model.

A Preoperative Nomogram to Predict Renal Function Insufficiency for Cisplatin-based Adjuvant Chemotherapy Following Minimally Invasive Radical Nephroureterectomy (ROBUUST Collaborative Group).

BACKGROUND: Postoperative renal function impairment represents a main limitation for delivering adjuvant chemotherapy after radical nephroureterectomy (RNU). OBJECTIVE: To create a model predicting renal function decline after minimally invasive RNU. DESIGN, SETTING, AND PARTICIPANTS: A total of 490 patients with nonmetastatic UTUC who underwent minimally invasive RNU were identified from a collaborative database including 17 institutions worldwide (February 2006 to March 2020). Renal function insufficiency for cisplatin-based regimen was defined as estimated glomerular filtration rate (eGFR) <50 ml/min/1.73 m2 at 3 mo after RNU. Patients with baseline eGFR >50 ml/min/1.73 m2 (n = 361) were geographically divided into a training set (n = 226) and an independent external validation set (n = 135) for further analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, a nomogram to predict postoperative eGFR <50 ml/min/1.73 m2 was built based on the coefficients of the least absolute shrinkage and selection operation (LASSO) logistic regression. The discrimination, calibration, and clinical use of the nomogram were investigated. RESULTS AND LIMITATIONS: The model that incorporated age, body mass index, preoperative eGFR, and hydroureteronephrosis was developed with an area under the curve of 0.771, which was confirmed to be 0.773 in the external validation set. The calibration curve demonstrated good agreement. Besides, the model was converted into a risk score with a cutoff value of 0.583, and the difference between the low- and high-risk groups both in overall death risk (hazard ratio [HR]: 4.59, p < 0.001) and cancer-specific death risk (HR: 5.19, p < 0.001) was statistically significant. The limitation mainly lies in its retrospective design. CONCLUSIONS: A nomogram incorporating immediately available clinical variables can accurately predict renal insufficiency for cisplatin-based adjuvant chemotherapy after minimally invasive RNU and may serve as a tool facilitating patient selection. PATIENT SUMMARY: We have developed a model for the prediction of renal function loss after radical nephroureterectomy to facilitate patient selection for perioperative chemotherapy.

The Prognostic Value of Lymphovascular Invasion in Patients With Upper Tract Urinary Carcinoma After Surgery: An Updated Systematic Review and Meta-Analysis.

Background and Purpose: Although the prognostic value of lymphovascular invasion (LVI) for upper tract urinary carcinoma (UTUC) has been reported, there is a lack of consensus regarding the prognostic factor of LVI in UTUC after radical nephroureterectomy (RNU). The aim of the present study was to evaluate the contemporary role of LVI using systematic review and meta-analysis. Materials and Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we performed a systematic search of Web of Science, PubMed, and EMBASE for all reports published up to July 2019. Cumulative analyses of hazard ratios (HRs)/odds ratios (ORs) and their corresponding 95% confidence intervals were conducted to assess the association between LVI and oncological outcomes and clinicopathological features. Results: Our meta-analysis included 31 eligible studies containing 14,653 patients with UTUC (81-1,363 per study). Our results indicated a significant correlation of LVI with worse cancer-specific survival (HR = 1.59, p < 0.001), overall survival (HR = 1.55, p < 0.001), recurrence-free survival (HR = 1.46, p < 0.001), cancer-specific mortality (HR = 1.25, p = 0.047), and recurrence (HR = 1.23, p = 0.026). LVI was also correlated with advanced tumor stage (III/IV vs. I/II: OR = 7.63, p < 0.001), higher tumor grade (3 vs. 1/2: OR = 5.61, p < 0.001), lymph node metastasis (yes vs. no: OR = 4.95, p < 0.001), carcinoma in situ (yes vs. no: OR = 1.92, p < 0.001), and positive surgical margin (yes vs. no: OR = 4.38, p < 0.001), but not related to gender (male vs. female: OR = 0.98, p = 0.825), and multifocality (multifocal vs. unifocal: OR = 1.09, p = 0.555). The funnel plot test indicated no significant publication bias. Conclusions: This study demonstrated that LVI was associated with aggressive clinicopathological features. LVI may serve as a poor prognostic factor for patients with UTUC after RNU.

Prognostic Value of Preoperative Hydronephrosis in Patients Undergoing Radical Nephroureterectomy for Upper Tract Urinary Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Several recent publications have evaluated the prognostic value of preoperative hydronephrosis (HN) in patients with upper tract urinary carcinoma (UTUC). The aim of this meta-analysis was to explore the pooled effect of preoperative HN on the prognosis of UTUC patients treated with radical nephroureterectomy (RNU) based on current evidence. METHODS: We performed a systematic search of Pubmed, Cochrane library, and Web of Science databases from inception to June 2020. The outcomes of interest included overall survival (OS), cancer-special survival (CSS), disease-free survival (DFS), and intravesical recurrence-free survival (IVRFS). RESULTS: Twenty-two studies with a total of 7,542 patients satisfied the eligibility criteria and were finally included in this meta-analysis. The percent of patients with preoperative HN varied in the eligible studies, ranging from 18 to 81%. The pooled results showed that preoperative HN was significantly associated with worse OS (P = 0.004), CSS (P < 0.001), and DFS (P = 0.005), but not IVRFS (P = 0.12). No obvious publication bias was detected by Begg's test in all the analyses. CONCLUSIONS: The results drawn in our meta-analysis suggest that the presence of preoperative HN is associated with worse prognosis in patients treated with RNU for UTUC. Therefore, closer surveillance and more aggressive therapy may be needed for UTUC patients present with preoperative HN. Well-designed prospective studies are necessary to substantiate the prognostic value of HN in UTUC.

A Urine-Based Liquid Biopsy Method for Detection of Upper Tract Urinary Carcinoma.

BACKGROUND: Conventional clinical detection methods such as CT, urine cytology, and ureteroscopy display low sensitivity and/or are invasive in the diagnosis of upper tract urinary carcinoma (UTUC), a factor precluding their use. Previous studies on urine biopsy have not shown satisfactory sensitivity and specificity in the application of both gene mutation or gene methylation panels. Therefore, these unfavorable factors call for an urgent need for a sensitive and non-invasive method for the diagnosis of UTUC. METHODS: In this study, a total of 161 hematuria patients were enrolled with (n = 69) or without (n = 92) UTUC. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel. Further, a logistic regression prediction model that contained several significant features was used to evaluate the risk of UTUC in these patients. RESULTS: In total, 86 UTUC- and 64 UTUC+ case samples were enrolled for the analysis. A logistic regression analysis of significant features including age, the mutation status of TERT promoter, and ONECUT2 methylation level resulted in an optimal model with a sensitivity of 94.0%, a specificity of 93.1%, the positive predictive value of 92.2% and a negative predictive value of 94.7%. Notably, the area under the curve (AUC) was 0.957 in the training dataset while internal validation produced an AUC of 0.962. It is worth noting that during follow-up, a patient diagnosed with ureteral inflammation at the time of diagnosis exhibiting both positive mutation and methylation test results was diagnosed with ureteral carcinoma 17 months after his enrollment. CONCLUSION: This work utilized the epigenetic biomarker ONECUT2 for the first time in the detection of UTUC and discovered its superior performance. To improve its sensitivity, we combined the biomarker with high-throughput sequencing of 17 genes test. It was found that the selected logistic regression model diagnosed with ureteral cancer can evaluate upper tract urinary carcinoma risk of patients with hematuria and outperform other existing panels in providing clinical recommendations for the diagnosis of UTUC. Moreover, its high negative predictive value is conducive to rule to exclude patients without UTUC.

Risk stratification of upper tract urothelial carcinoma: A Review of the Current Literature.

Introduction: Several prognostic factors have been identified to risk stratify patients with upper tract urothelial carcinoma (UTUC). However, due to the heterogeneity of these prognosticators and the presence of different therapeutic modalities for this rare and heterogeneous disease, decision-making and patient consulting remains challenging. Areas covered: A literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted in January 2019 to find relevant English-language studies identifying prognostic factors that can help risk stratify patients and select proper therapeutic modality. Expert opinion: Several studies confirmed the value of patient and tumor-related factors for prognosticating oncological outcomes in UTUC patients. However, due to the retrospective nature of these studies, the true clinical impact needs to be assessed in well-designed prospective-controlled studies to increase the accuracy and fortify the evidence-driven clinical decision-making process. More biomarkers studies for stratifying risks of UTUC patients are needed to capture their biologic and clinical potentials of each individual tumor.

Prevalence, clinicopathological features, and prognosis in upper tract urinary carcinoma patients with severe preoperative chronic kidney disease.

BACKGROUND: Studies regarding the prevalence and factors associated with severe pre-operative chronic kidney disease (CKD) in upper tract urinary carcinoma (UTUC) patients were rare due to the low prevalence of UTUC. We conducted the present study to investigate the prevalence, clinicopathological features, and prognosis in UTUC patients with severe preoperative CKD. METHODS: The study included 731 patients with UTUC treated with radical nephroureterectomy (RNU) in a large Chinese center. Estimated glomerular filtration rate (eGFR) was calculated by re-expressed Modification of Diet in Renal Disease (MDRD) formulas for the Chinese population. Severe preoperative CKD was defined as CKD stage 4-5 (eGFR <30 mL/min). Relationships of CKD stage 4-5 with clinicopathological characteristics, overall survival (OS), cancer-specific survival (CSS), contralateral recurrence-free survival and intravesical recurrence (IVR)-free survival were analyzed. RESULTS: A total of 73 (10.0%) patients presented severe preoperative CKD in this cohort. Multivariate logistic analysis indicated that female gender (OR =1.791; 95% CI: 1.018-3.150; P=0.043), lower BMI (OR =0.452; 95% CI: 0.262-0.778; P=0.004), concomitant bladder tumor (OR =2.944; 95% CI: 1.360-6.373; P=0.006), lower pathological T stage (OR =0.578; 95% CI: 0.339-0.984; P=0.043), tumor necrosis (OR =2.764; 95% CI: 1.411-5.416; P=0.003), and exposure of aristolochic acid (AA) (OR =3.115; 95% CI: 1.536-6.316; P=0.002) were significantly related to severe CKD. Multivariate Cox's regression analysis showed that severe preoperative CKD was significantly associated with worse OS (HR =1.840; 95% CI: 1.150-2.944; P=0.011) and worse contralateral recurrence-free survival (HR =3.269; 95% CI: 1.607-6.650; P=0.001), while no statistical difference in terms of CSS or IVR-free survival were noticed. CONCLUSIONS: Female gender, lower BMI, concomitant bladder tumor, lower pathological T stage, exposure of AA, and tumor necrosis were independently associated with severe preoperative CKD in UTUC patients. UTUC patients with severe preoperative CKD possess worse OS and higher possibility of contralateral upper urinary tract recurrence.