First Report of Oncological Outcome and Prognostic Analysis in a First-Line Setting of Short Hydration Gemcitabine and Cisplatin Chemotherapy for Patients with Metastatic Urothelial Carcinoma.

OBJECTIVES: The aim of the study was to examine the effectiveness of a modified-short hydration gemcitabine and cisplatin (m-shGC) regimen for patients with metastatic urothelial carcinoma (mUC) and to assess the efficacy of a geriatric nutritional risk index (GNRI) with regard to prognosis. PATIENTS AND METHODS: From January 2016 to July 2020, 68 patients with mUC underwent first-line m-shGC therapy with 70 mg/m2 cisplatin and 1,000 mg/m2 gemcitabine (days 1, 8, and 15), with 2,050 mL fluid replaced on the first day of each 28-day cycle. Prior to the start of treatment, the serum neutrophil-to-lymphocyte ratio (NLR), and levels of albumin and C-reactive protein (CRP) in serum, as well as body heights and weights were measured. Patients were grouped according to GNRI <92 (low) or ≥92 (high). The analysis of data was done retrospectively. RESULTS: Median follow-up was found to be 12.9 (range 1.7-50.2) months and the objective response rate (ORR) was 54.4% after m-shGC treatment. The ORR was significantly different when high and low-GNRI groups were compared (ORR: 28.0 vs. 69.8% in low- vs. high-GNRI groups). Median overall survival (OS) was calculated as 8.6 (95% confidence interval [CI]: 5.4-21.3) and 34.5 (95% CI: 20.5-NA) months for low- and high-GNRI groups, respectively (p < 0.0001). Unlike for NLR and CRP, univariate and multivariate analyses revealed that low GNRI and visceral metastases were significant prognostic factors for short OS. CONCLUSIONS: First-line m-shGC showed a survival benefit for mUC, with GNRI a useful prognostic biomarker.

N-glycan signature of serum immunoglobulins as a diagnostic biomarker of urothelial carcinomas.

Discriminating between urothelial carcinoma (UC), including bladder cancer (BCa) and upper urinary tract UC (UTUC), is often challenging. Thus, the current study evaluated the diagnostic performance of N-glycosylation signatures of immunoglobulins (Igs) for detecting UC, including BCa and UTUC. N-glycosylation signatures of Igs from serum samples of the training cohort, including 104 BCa, 68 UTUC, 10 urinary tract infection, and 5 cystitis cases, as well as 62 healthy volunteers, were measured retrospectively using automated capillary-electrophoresis-based N-glycomics. UTUC or BCa scores were then established through discriminant analysis using N-glycan signatures of Igs. Diagnostic performance was evaluated using the area under receiver operating characteristics curve (AUC) and decision curve analyses (DCA). Our result showed that BCa and UTUC scores for discriminating BCa (AUC: 0.977) and UTUC (AUC: 0.867), respectively, provided significantly better clinical performance compared to urine cytology, gross hematuria, or clinical T1 cases. DCA revealed that adding BCa and UTUC scores to gross hematuria status was the best combination for detecting UC and avoiding the need for more intervention without overlooking UC (risk threshold: 13%-93%). The UC nomogram based on the combination of gross hematuria, UTUC score, and BCa score could detect UC with an AUC of 0.891, indicating significantly better performance compared to gross hematuria status in the validation cohort (251 patients). The limitations of this study include its small sample size and retrospective nature. The UC nomogram based on gross hematuria and N-glycosylation signatures of Igs can be a promising approach for the diagnosis of UC.

Pre-therapy serum albumin-to-globulin ratio in patients treated with neoadjuvant chemotherapy and radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: The accurate selection of patients who are most likely to benefit from neoadjuvant chemotherapy is an important challenge in oncology. Serum AGR has been found to be associated with oncological outcomes in various malignancies. We assessed the association of pre-therapy serum albumin-to-globulin ratio (AGR) with pathologic response and oncological outcomes in patients treated with neoadjuvant platin-based chemotherapy followed by radical nephroureterectomy (RNU) for clinically non-metastatic UTUC. METHODS: We retrospectively included all clinically non-metastatic patients from a multicentric database who had neoadjuvant platin-based chemotherapy and RNU for UTUC. After assessing the pretreatment AGR cut-off value, we found 1.42 to have the maximum Youden index value. The overall population was therefore divided into two AGR groups using this cut-off (low, < 1.42 vs high, ≥ 1.42). A logistic regression was performed to measure the association with pathologic response after NAC. Univariable and multivariable Cox regression analyses tested the association of AGR with OS and RFS. RESULTS: Of 172 patients, 58 (34%) patients had an AGR < 1.42. Median follow-up was 26 (IQR 11-56) months. In logistic regression, low AGR was not associated with pathologic response. On univariable analyses, pre-therapy serum AGR was neither associated with OS HR 1.15 (95% CI 0.77-1.74; p = 0.47) nor RFS HR 1.48 (95% CI 0.98-1.22; p = 0.06). These results remained true regardless of the response to NAC. CONCLUSION: Pre-therapy low serum AGR before NAC followed by RNU for clinically high-risk UTUC was not associated with pathological response or long-term oncological outcomes. Biomarkers that can complement clinical factors in UTUC are needed as clinical staging and risk stratification are still suboptimal leading to both over and under treatment despite the availability of effective therapies.

Prognostic significance of the albumin-to-globulin ratio for upper tract urothelial carcinoma.

BACKGROUND: Although the albumin-to-globulin ratio (AGR) is a promising biomarker for various malignancies, few studies have investigated its prognostic significance for upper tract urothelial carcinoma (UTUC). METHODS: This retrospective study conformed to the REporting recommendations for tumour MARKer prognostic studies (REMARK) guideline. We reviewed 179 patients with UTUC who underwent radical nephroureterectomy at our institution between 2008 and 2018. Associations of preoperative clinicopathological factors, including the AGR, with cancer-specific survival (CSS) and overall survival (OS) were assessed. The Cox proportional hazards model was used for univariate and multivariable analyses. AGR was dichotomized as < 1.25 and ≥ 1.25, according to the most discriminatory cutoff determined from the receiver operating characteristic curve analysis. RESULTS: During a median follow-up of 34 months after surgery, 37 patients died from UTUC and 13 died of other causes. The preoperative AGR significantly correlated with pathological T stage, pathological N stage, and adjuvant chemotherapy. Multivariate analyses demonstrated that a decreased (< 1.25) preoperative AGR was an independent poor prognostic factor for both CSS (hazard ratio [HR] = 2.81, P <  0.01) and OS (HR = 2.09, P <  0.05). CONCLUSIONS: Preoperative AGR < 1.25 might serve as a useful prognostic marker for patients with UTUC undergoing radical nephroureterectomy.

Prognostic role of preoperative De Ritis ratio in upper tract urothelial carcinoma treated with nephroureterectomy.

PURPOSE: To validate the predictive and prognostic role of the De Ritis ratio in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy in a large multi-institutional cohort. MATERIALS AND METHODS: The preoperative De Ritis ratio was assessed in a multi-institutional cohort of 2,492 patients. An altered De Ritis ratio was defined as a ratio >1.35. Logistic regression analyses were performed to assess the association of the De Ritis ratio with advanced disease. The association of the De Ritis ratio with survival outcomes was evaluated using Cox proportional hazards regression models. RESULTS: An altered De Ritis ratio was observed in 985 (41.5%) patients; it was associated with a more advanced pathological features. In a preoperative model, the De Ritis ratio was an independent predictive factor for the presence of lymph node metastasis and muscle-invasive and nonorgan-confined disease (P < 0.05). Compared to patients with a normal De Ritis ratio, those with an altered De Ritis ratio had worse recurrence free (P <0.0001), cancer specific (P = 0.0003), and overall survival (P = 0.0014) in the Kaplan-Meier analyses. In the multivariable analyses that was adjusted for the effects of standard clinicopathologic features, the De Ritis ratio did not retain its independent prognostic value. CONCLUSIONS: In UTUC, the preoperative De Ritis ratio is associated with adverse clinicopathologic features and independently predicts features of biologically and clinically aggressive UTUC. Therefore, it might be useful to incorporate the De Ritis ratio into prognostic tools in selecting appropriate treatment strategies.

The pretreatment neutrophil-to-lymphocyte ratio is a novel biomarker for predicting clinical responses to pembrolizumab in platinum-resistant metastatic urothelial carcinoma patients.

PURPOSE: We investigated the relationship between pretreatment neutrophil-to-lymphocyte ratio (pre-NLR) levels just before the initiation of treatment with pembrolizumab and clinical outcomes in platinum-resistant metastatic urothelial carcinoma (UC) patients treated with pembrolizumab. METHODS: Our study population comprised 78 patients diagnosed with metastatic UC and treated with pembrolizumab after platinum-based chemotherapy at our institutions between December 2017 and April 2019. We examined the relationships between pre-NLR levels just before pembrolizumab treatment and clinical outcomes. A pre-NLR level of ≥3.35 was defined as elevated according to a calculation by a receiver-operating curve analysis. RESULTS: The high pre-NLR group consisted of 33 patients (42.3%). Overall, 29.5% of patients had a clinical response and the sum of the target lesion longest diameter was decreased in 18.8% of the high pre-NLR group, which was significantly lower than that in the low pre-NLR group (58.1%, P = 0.005). Six-month progression-free survival and cancer-specific survival rates for the high pre-NLR group were 9.1 and 58.0%, which were significantly lower than those for their counterpart (45.9 and 89.1%, P < 0.001 and P = 0.002, respectively). The pre-NLR level was an independent indicator of disease progression and cancer-specific death (P < 0.001 and P = 0.003). Furthermore, patients with a postpembrolizumab NLR level that had decreased ≥25% from the pre-NLR level had significantly lower disease progression and cancer-specific death rates than their counterparts (P = 0.01 and P = 0.022, respectively). CONCLUSIONS: Elevated pre-NLR may be a novel biomarker for identifying poor responders to pembrolizumab among platinum-resistant metastatic UC patients.

Prognostic value of preoperative blood-based biomarkers in upper tract urothelial carcinoma treated with nephroureterectomy: A systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis assessed the prognostic value of preoperative blood-based biomarkers in patients with upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy. METHODS: PUBMED, Web of Science, Cochrane Library, and Scopus databases were searched in June 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared cancer-specific survival in UTUC patients with and without pretreatment laboratory abnormalities. Formal meta-analyses were performed for this outcome. RESULTS: The review identified 54 studies with 23,118 patients, of these, 52 studies with 22,513 patients were eligible for the meta-analysis. Several preoperative blood-based biomarkers were significantly associated with cancer-specific survival as follows: neutrophil-lymphocyte ratio (pooled hazard ratio [HR]: 1.66, 95% confidence interval [CI]: 1.34-2.06), C-reactive protein (pooled HR: 1.17, 95% CI: 1.07-1.29), platelet-lymphocyte ratio (pooled HR: 1.68, 95% CI: 1.30-2.17), white blood cell (pooled HR: 1.58, 95% CI: 1.02-2.46), De Ritis ratio (pooled HR: 2.40, 95% CI: 1.92-2.99), fibrinogen (pooled HR: 2.23, 95% CI: 1.86-2.68), albumin-globulin ratio (pooled HR: 3.00, 95% CI: 1.87-4.84), hemoglobin (pooled HR: 1.51, 95% CI: 1.22-1.87), and estimate glomerular filtration rate (pooled HR: 1.52, 95% CI: 1.19-1.94). The Cochrane's Q test and I2 test revealed significant heterogeneity for neutrophil-lymphocyte ratio, C-reactive protein, white blood cell, hemoglobin, and estimated glomerular filtration rate (P = 0.022; I2 = 50.7%, P = 0.000; I2 = 80.4%, P = 0.000; I2 = 88.3%, P = 0.010; I2 = 62.0%, P = 0.000; I2 = 83.9%, respectively). CONCLUSIONS: Several pretreatment laboratory abnormalities in patients with UTUC were associated with increased risks of cancer-specific mortality. Therefore, blood-based biomarkers may have the potential to serve as prognostic factors to assist patients and physicians in selecting appropriate treatment strategies for UTUC. However, considering the study limitations including heterogeneity and retrospective nature of the primary data, the conclusions should be interpreted with caution.

Serum Hepcidin and GDF-15 levels as prognostic markers in urothelial carcinoma of the upper urinary tract and renal cell carcinoma.

BACKGROUND: Cancer is a life-threatening disease that causes every fourth death. It is often hard to determine the time point of progression. Therefore, biomarkers for cancer entities that indicate disease progression or aggressiveness and thereby guide therapeutic decisions are required. Unfortunately, reliable biomarkers are rare. In this study, the potential of serum hepcidin and serum GDF-15 as biomarkers that correlate with patient's survival in the two entities upper urinary tract urothelial carcinomas (UUTUC) and renal cell carcinoma (RCC) were analyzed. METHODS: In this retrospective study n = 38 patients suffering from UUTUC, n = 94 patients suffering from RCC and n = 21 patients without infections or cancer, all hospitalized at the University Hospital Muenster, were included. Serum samples of patients were retrospectively analyzed. Serum hepcidin and GDF-15 levels were measured and correlated to aggressiveness and progression of the disease as well as patient's outcome. RESULTS: For both entities, UUTUC and RCC, serum hepcidin levels as well as serum GDF-15 levels were increased compared to sera of controls. High serum hepcidin and GDF-15 levels were associated with metastases and cancer relapse. Also, in both entities, the overall survival was decreased in patients with increased serum hepcidin and GDF-15 levels. Hence, high serum hepcidin and GDF-15 levels correlated with patient's outcome. CONCLUSION: To conclude, the data of this study show a correlation of high serum hepcidin and GDF-15 levels with aggressiveness and progression of the disease and demonstrate potential prognostic properties of serum hepcidin and GDF-15 levels. The data support the further assessment of serum hepcidin and GDF-15 as prognostic markers in RCC and UUTUC.

Alteration in serum concentrations of FGF19, FGF21, and FGF23 in patients with urothelial carcinoma.

Fibroblast growth factors (FGF) 19, 21, and 23 have been reported as functional factors in human metabolic diseases and malignancies. We performed a prospective survey to compare circulating FGF levels in urothelial carcinoma (UC) patients and normal controls. Between 2016 and 2017, 39 patients with UC of the urinary bladder or upper urinary tract who received surgical intervention were included. All the serum samples were obtained before surgeries. The control group included 28 healthy volunteers. Analysis of the circulating FGF19, 21, and 23 levels among all 67 subjects, as well as a subgroup analysis of the 39 UC patients were performed. The median levels of serum FGF19, 21, and 23 in the UC patients were 84.2, 505.3, and 117.6 pg/mL, respectively, which were statistically different from levels found in the healthy controls (P = 0.015, <0.001 and < 0.001, respectively). In the subgroup analysis, the FGF19 and FGF21 levels were significantly higher in end-stage renal disease UC patients, while FGF21 was also higher in the UC patients with cardiovascular diseases and history of recurrent UC. In the receiver operating characteristic (ROC) curve analysis, FGF19, 21, and 23 were all significant predictors of UC [area under the curve (AUC)] 0.674, P = 0.015; AUC 0.918, P < 0.001; AUC 0.897, P < 0.001, respectively). In UC patients, serum FGF19 level was significantly lower, while FGF21 and 23 were significantly higher, than respective levels in healthy controls. All three markers may serve as good predictors of UC occurrence, and FGF21 level was associated with disease recurrence. © 2018 BioFactors, 45(1):62-68, 2019.

The prognostic value of PD-L1 expression in upper tract urothelial carcinoma varies according to platelet count.

Programmed cell death ligand-1 (PD-L1) is a ligand for programmed cell death-1 (PD-1) that negatively regulates T-cell activation and plays a crucial role in suppressing anti-tumor host immunity. Although PD-L1 is a promising immunotherapy target in various cancers, including urothelial carcinoma (UC), the prognostic significance of PD-L1 in UC is unclear. As platelets help protect tumor cells from immune elimination in the circulatory system, we hypothesized that tumor PD-L1 and circulating platelets might synergistically promote tumor metastasis, and that the prognostic significance of PD-L1 might vary according to platelet count. We immunohistochemically examined tumor PD-L1 expression in 271 patients with upper tract UC, which revealed PD-L1 positivity in 31 of 271 cases (11%). The associations of tumor PD-L1 expression with outcomes varied among patients with high or low platelet counts (Pinteraction  < 0.004). Among patients with high platelet counts (N = 136), PD-L1 positivity (N = 15) was significantly associated with shorter metastasis-free survival (univariate hazard ratio [HR]: 6.23, 95% confidence interval [CI]: 2.95-13.1; multivariate HR: 2.68, 95% CI: 1.27-5.64) and shorter overall survival (univariate HR: 4.92, 95% CI: 2.14-11.3, multivariate HR: 2.78, 95% CI: 1.19-6.51). In contrast, among patients with low platelet counts (N = 135), PD-L1 positivity (N = 16) was not significantly associated with these outcomes. Our results suggest that tumor PD-L1 expression and platelet count might interact and help regulate tumor progression. Although a larger prospective study is needed to validate our findings, this relationship is important to consider, as immunotherapies targeting the PD-1/PD-L1 axis have gained significant attention as promising therapies for UC.

Prognostic role of the preoperative serum albumin : globulin ratio after radical nephroureterectomy for upper tract urothelial carcinoma.

OBJECTIVES: To elucidate the effects of the preoperative albumin : globulin ratio on the survival of patients with upper tract urothelial carcinoma after radical nephroureterectomy. METHODS: We retrospectively reviewed 124 consecutive patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy at Chiba Cancer Center, Chiba, Japan between 2002 and 2015. The albumin : globulin ratio was defined: albumin / (total protein - albumin). Associations between preoperative clinicopathological factors, including the albumin : globulin ratio, and recurrence-free survival, cancer-specific survival and overall survival were assessed. The log-rank test and Cox proportional hazards models were used for univariate and multivariable analyses, respectively. The study cohort was separated into two groups based on the optimal albumin : globulin ratio cut-off value determined using receiver operating characteristic curve analysis. RESULTS: The median survival time was 55 months (interquartile range 28-76 months), and 31 patients died during follow up. A low preoperative albumin : globulin ratio <1.40 was associated with tumor grade and surgical margin status. Kaplan-Meier analyses showed that a low albumin : globulin ratio was more significantly correlated with worse recurrence-free survival, cancer-specific survival and overall survival. Multivariate analyses showed that a low albumin : globulin ratio was an independent predictive factor associated with poor recurrence-free survival (hazard ratio 3.758; P = 0.0028), cancer-specific survival (hazard ratio 5.687; P = 0.0044) and overall survival (hazard ratio 3.124; P = 0.0030). CONCLUSIONS: A low albumin : globulin ratio is an independent predictive factor associated with poor prognosis in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

Prognostic Impact of Preoperative Albumin-Globulin Ratio on Oncologic Outcomes in Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy.

PURPOSE: To identify the impact of albumin-globulin ratio (AGR) on pathologic and survival outcomes in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). PATIENTS AND METHODS: We retrospectively reviewed medical records of 620 patients treated with RNU for UTUC at our institution. Logistic regression analysis was used to evaluate the relation between low AGR (<1.45) and adverse pathologic features. Kaplan-Meier curves were used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) probabilities between 2 groups. Univariable and multivariable Cox regression models were performed to address prognostic factors related to RFS, CSS, and OS. RESULTS: Of the 620 patients, 323 (52.1%) had AGR < 1.45. During a median follow-up of 50.0 months (interquartile range, 28-78 months), 277 (44.7%) experienced disease recurrence and 194 (31.3%) died of disease. The results showed that low AGR was significantly associated with adverse pathologic features (all P < .05). Kaplan-Meier analysis showed that compared to those with high AGR (≥1.45), patients with low AGR had poorer RFS, CSS, and OS (P < .001). After adjusting for the confounding clinicopathologic factors, multivariate analyses showed that AGR < 1.45 independently predicted poor RFS (hazard ratio [HR] = 1.321, P = .029), CSS (HR = 1.503, P = .010) and OS (HR = 1.403, P = .015). CONCLUSION: Low preoperative AGR is an independent predictor of worse pathologic and oncologic outcomes in patients with UTUC after RNU. The application of AGR as an easily assessed blood-based biomarker in predicting the prognosis of patients with UTUC is promising.

Preoperative Low Lymphocyte-to-Monocyte Ratio Predicts Poor Clinical Outcomes for Patients with Urothelial Carcinoma of the Upper Urinary Tract.

PURPOSE: Urothelial carcinoma of the upper urinary tract (UUTUC) is a rare genitourinary tumor. Pre-operative lymphocyte-to-monocyte ratio (LMR) is associated with worse outcome in several malignancies. The aim of this study was to determine the prognostic value of pre-operative LMR in UUTUC. MATERIALS AND METHODS: A historical cohort of 100 UUTUC patients was recruited from January 1990 to June 2011. The counts of peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated by dividing lymphocyte count by monocyte count. Receiver operating characteristic curve (ROC) analysis, Log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses to evaluate theassociations of LMR with overall survival (OS) and disease-free survival (DFS). RESULT: Univariate analysis revealed that low level of LMR (? 3.0) was significantly associated with worse OS (P = .024) but not DFS (P = .993). Multivariate Cox proportional hazard analysis showed that low level of LMR was a significantly independent predictor for worse OS (hazard ratio = 0.366, 95% confident interval: 0.180-0.744). Based on the results of multivariate analysis, the rates of OS at 5 years developed by the prognostic model were asfollows: low risk, 88.0%, intermediate risk, 44.0%, and high risk, 13.0%, respectively. CONCLUSION: The pre-operative LMR serves an independent prognostic biomarker in UUTUC. The prognostic model based on the LMR and pathologic factors can be available in selection of high risk patients for further aggressive therapy.

Prognostic Value of Albumin/Globulin Ratio in Patients with Upper Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy.

BACKGROUND/AIM: We investigated the prognostic role of the albumin/globulin ratio (AGR) in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). PATIENTS AND METHODS: AGR was calculated as follows: AGR=serum albumin/(serum total protein-serum albumin). Associations of preoperative AGR with disease-free (DFS) and overall (OS) survival were assessed in 105 patients with UTUC undergoing RNU. RESULTS: Patients with preoperative AGR <1.24 and ≥1.24 were classified into the low (n=46, 44%) and high (n=59, 56%) groups, respectively. The 5-year DFS and OS were 77% and 78%, respectively. On multivariate analysis, high preoperative AGR was an independent predictor for both better DFS (hazard ratio(HR)=0.34, p=0.038) and OS (HR=0.24, p=0.006). The 5-year DFS and OS were significantly longer in the high-AGR group than in the low-AGR group (90% vs. 60%; 89% vs. 65%, both p<0.001). CONCLUSION: The AGR has prognostic value in patients with UTUC undergoing RNU.

Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients.

BACKGROUND: Preoperative blood-based inflammatory biomarkers have been suggested to improve staging and prognostication in patients with upper-tract urothelial carcinoma (UTUC). Neutrophil-to-lymphocyte ratio (NLR) is the most studied blood-based biomarker. NLR is an indicator of systemic inflammation and has been shown to be associated with a poor prognosis in various malignancies. The aim of this study was to analyze the current evidence regarding the prognostic significance of preoperative NLR in patients undergoing radical nephroureterectomy (RNU) for UTUC to assess its prognostic potential. MATERIALS AND METHODS: A systematic search of Web of Science, Medline/PubMed and Cochrane library was performed on the 1st of October, 2017. Studies were deemed eligible if they compared patients with high NLR before surgical treatment for UTUC to patients with low NLR to determine its predictive value for survival using multivariable logistic regression analysis. We performed a formal meta-analysis for cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS). RESULTS: Nine studies including a total of 4385 patients assessing the importance of NLR were included in this meta-analysis. The cut-off NLR varied in the eligible studies ranging from 2 to 3. Increased pretreatment NLR predicted OS (pooled HR 1.64 95% CI; 1.23-2.17), RFS (pooled HR 1.60 95% CI; 1.16-2.20) and CSS (pooled HR 1.73 95% CI; 1.23-2.44) in multivariable analyses. CONCLUSION: In this meta-analysis, preoperative blood-based NLR is associated with worse prognosis in patients who underwent RNU for UTUC. NLR could be used to improve clinical decision making regarding RNU vs. kidney-sparing surgery, extent of lymphadenectomy, perioperative systemic therapy and follow-up schedule.

Timing of blood transfusion and oncologic outcomes in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate the impact of timing of blood transfusion in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). METHODS: Outcomes of consecutive patients with UTUC treated with RNU were analyzed. Clinicopathologic factors were compared using Fisher's exact test or the Wilcoxon rank-sum test between patients who received any transfusion and no transfusion, and between patients receiving intraoperative transfusion only and patients receiving no transfusion. Cancer-specific and overall survival were estimated and multivariable analyses were performed to assess the impact of timing of transfusion on clinical outcomes. RESULTS: Among 402 patients included in this study, 71 (17.6%) patients received a transfusion at any point and 27 (6.7%) patients received an intraoperative blood transfusion. Transfusion at any time, patient comorbidity, high grade, advanced stage, positive surgical margins, low preoperative hemoglobin, longer operative duration, and increased blood loss were significantly associated with cancer-specific survival (DSS) on univariable analysis (HR 1.85, 95% CI 1.20-2.85, p < 0.005). In the multivariable analysis, transfusion at any point was not a prognostic factor (HR 1.00, 95% CI 0.60-1.68, p = 0.99). When examining intraoperatively transfusion only, transfusion was significantly associated with DSS (HR 1.91, 95% CI 1.01-3.59, p = 0.045) but no longer significant in multivariable analysis (HR 0.72, 95% CI 0.32-1.65, p = 0.440). CONCLUSIONS: Our study indicates that the administration of blood transfusion either intraoperatively or postoperatively is not associated with clinical or oncological outcomes in patients with upper tract urothelial carcinoma when adjusted for other factors in multivariable analysis. Further study is required.

The De Ritis (aspartate transaminase/alanine transaminase) ratio as a predictor of oncological outcomes in patients after surgery for upper urinary tract urothelial carcinoma.

PURPOSE: Recently, several studies have shown that the De Ritis ratio (aspartate transaminase/alanine transaminase) can be a useful prognostic biomarker for certain types of malignant tumors. However, the prognostic value of the De Ritis ratio in patients with upper tract urothelial carcinoma remains largely unknown. The aim of the present study was to evaluate the prognostic significance of the De Ritis ratio in patients who had undergone radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma. METHODS: In total, 1049 patients who underwent RNU at eight institutions from 2004 to 2015 were reviewed retrospectively. The De Ritis ratio and conventional clinicopathological parameters were analyzed. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis was carried out using the Cox proportional hazards regression model. De Ritis ratio cutoff values were derived from receiver operating characteristic (ROC) curves. RESULTS: ROC analysis showed the cutoff De Ritis ratio for overall death to be 1.6 (p = 0.002). The cancer-specific survival (CSS) and overall survival (OS) were significantly shorter for patients with a high De Ritis ratio (>1.6). Multivariate analysis revealed an independent relationship between an increased De Ritis ratio (>1.6) and shorter CSS (hazard ratio, HR 2.49, 95% confidence interval, CI 1.70-3.64; p = 0.001) and OS (HR 1.84, 95% CI 1.34-2.52; p = 0.001). CONCLUSION: The De Ritis ratio can be a significant predictor of oncological outcomes in patients with upper urinary tract urothelial carcinoma after surgery.

Preoperative serum pre-albumin as an independent prognostic indicator in patients with localized upper tract urothelial carcinoma after radical nephroureterectomy.

PURPOSE: To investigate the prognostic value of preoperative pre-albumin and albumin level in patients with localized upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy. METHODS AND MATERIALS: Between January 2003 and June 2013, we evaluated data on 425 patients with nonmetastatic UTUC (Ta-4N0/+M0) who underwent radical nephroureterectomy at our institution. Low pre-albumin level was defined as <20 mg/dl, while hypoalbuminemia was defined as albumin <35 g/L. The associations of preoperative low pre-albumin level and hypoalbuminemia with clinical and pathologic variables were assessed. Univariable and multivariable analyses using the Cox regression model were performed to determine prognostic factors that were associated with cancer specific survival (CSS) and overall survival (OS). The Harrell concordance index with variables only or combined pre-albumin data were used to evaluate the prognostic accuracy. RESULTS: Compared with patients with high pre-albumin level, patients with low pre-albumin level were more likely to have older age, higher tumor stage, higher rate of diabetes, regional lymph node metastasis and lymphovascular invasion. Meanwhile, hypoalbuminemia was only associated with diabetes. Multivariate analysis identified decreased preoperative pre-albumin level as an independent prognostic factor for CSS (HR 1.85, 95% CI 1.14-3.00, p=0.013) and OS (HR 1.73, 95% CI 1.12-2.70, p=0.015), but not preoperative hypoalbuminemia. The estimated c-index of the multivariate model for CSS and OS increased from 0.771 and 0.760 without pre-albumin to 0.775 and 0.765 when pre-albumin added. CONCLUSIONS: Low preoperative pre-albumin level but not preoperative hypoalbuminemia is a negative independent prognostic factor for survival outcome in patients with UTUC undergoing radical nephroureterectomy.

The neutrophil-to-lymphocyte ratio as a predictor of intravesical recurrence in patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with recurrence and poor prognosis in numerous cancer types. The aim of this study was to evaluate the use of the NLR as a biomarker for intravesical recurrence (IVR) in patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC) for the first time. METHODS: We retrospectively analyzed the records of 100 patients with UTUC who had undergone RNU between 1999 and 2015 at our institution. The association between the preoperative NLR and IVR were assessed using multivariate models. RESULTS: Among the 100 patients enrolled in the study, 33 developed IVR during a median follow-up of 34 months. The receiver operating characteristic analysis revealed that the optimum cut-off value for the preoperative NLR was >3.8. A high preoperative NLR (n = 21) was associated with a significantly increased risk of lymph node involvement (p = 0.036) and IVR (p = 0.034) compared with a low preoperative NLR (n = 79). IVR-free survival in patients with a high preoperative NLR was significantly worse than that of patients with a low preoperative NLR (p = 0.018). On multivariate analysis, the preoperative NLR [hazard ratio (HR) 2.49; p = 0.015] and tumor multifocality (HR 2.96; p = 0.024) were independent risk factors predictive of IVR. CONCLUSION: In our study population of patients with UTUC who had undergone RNU the preoperative NLR was associated with a significantly increased risk of IVR, suggesting that the NRL could be a useful biomarker for predicting IVR.