Impact of the controlling nutritional status (CONUT) score on perioperative morbidity and oncological outcomes in patients with bladder cancer treated with radical cystectomy

Introduction and objectivesTo evaluate the impact of the Controlling Nutritional Status (CONUT) score on perioperative morbidity and oncological outcomes of bladder cancer (BC) patients treated with radical cystectomy (RC).Materials and MethodsWe retrospectively analyzed a multi-institutional cohort of 347 patients treated with RC for clinical-localized BC between 2005 and 2019. The CONUT-score was defined as an algorithm including serum albumin, total lymphocyte count, and cholesterol. Multivariable logistic regression analyses were performed to evaluate the ability of the CONUT-score to predict any-grade complications, major complications and 30 days readmission. Multivariable Cox’ regression models were performed to evaluate the prognostic effect of the CONUT-score on recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS).ResultsA cut-off value to discriminate between low and high CONUT-score was determined by calculating the receiver operating characteristic (ROC) curve. The area under the curve was 0.72 hence high CONUT-score was defined as ≥3 points. Overall, 112 (32.3%) patients had a high CONUT. At multivariable logistic regression analyses, high CONUT was associated with any-grade complications (OR 3.58, P = 0.001), major complications (OR 2.56, P = 0.003) and 30 days readmission (OR 2.39, P = 0.01). On multivariable Cox' regression analyses, high CONUT remained associated with worse RFS (HR 2.57, P < 0.001), OS (HR 2.37, P < 0.001) and CSS (HR 3.52, P < 0.001).ConclusionsPoor nutritional status measured by the CONUT-score is independently associated with a poorer postoperative course after RC and is predictive of worse RFS, OS, and CSS. This simple index could serve as a comprehensive personalized risk-stratification tool identifying patients who may benefit from an intensified regimen of supportive cares.     

Prognostic value of the systemic inflammation modified Glasgow prognostic score in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy: Results from a large multicenter international collaboration

Introduction and objectivesTo evaluate the prognostic role of modified Glasgow prognostic score (mGPS) for the prediction of oncological outcomes in a retrospective large multicenter cohort of upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy (RNU).Materials and methodsWe retrospectively analyzed a multicenter cohort of patients treated with RNU for clinically nonmetastatic UTUC. Multivariable logistic regression analyses were performed to evaluate the ability of mGPS to predict nonorgan confined (NOC) disease and lymph-node involvement (LNI) at RNU. Multivariable Cox-regression models were performed to evaluate the preoperative and postoperative prognostic effect of mGPS on survival outcomes.ResultsOverall, 2,492 patients were included in the study. Of these, 1,929 (77%), 530 (21%), and 33 (1%) had a mGPS of 0, 1, and 2, respectively. mGPS was associated with characteristics of tumor aggressiveness and independently predicted LNI and NOC at RNU (both P < 0.05). On univariable and multivariable Cox-regression analyses, higher mGPS was independently associated with recurrence-free, cancer-specific, and overall survival, both in a preoperative and in a postoperative setting. The inclusion of mGPS significantly improved the discrimination of a preoperative model for the prediction of oncologic outcomes compared to standard prognosticators.ConclusionsWe found that mGPS is independently associated with clinicopathologic features and survival outcomes after RNU. Future studies should investigate the role of mGPS in a panel of preoperative markers for the prediction of NOC and LNI in UTUC patients, thus possibly improving the selection for perioperative systemic therapy.     

Association of preoperative serum De Ritis ratio with oncological outcomes in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

PurposeIdentifying which patients are likely to benefit from cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is important. We tested the association between preoperative serum De Ritis ratio (DRR, Aspartate Aminotransferase/Alanine Aminotransferase) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.Material and methodsmRCC patients treated with CN at different institutions were included. After assessing for the optimal pretreatment DRR cut‐off value, we found 1.2 to have the maximum Youden index value. The overall population was therefore divided into 2 DRR groups using this cut‐off (low, <1.2 vs. high, ≥1.2). Univariable and multivariable Cox regression analyses tested the association between DRR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel's concordance index (C-index). The clinical value of the DRR was evaluated with decision curve analysis.ResultsAmong 613 mRCC patients, 239 (39%) patients had a DRR ≥1.2. Median follow-up was 31 (IQR 16–58) months. On univariable analysis, high DRR was significantly associated with OS (hazard ratios [HR]: 1.22, 95% confidence interval [CI]: 1.01–1.46, P = 0.04) and CSS (HR: 1.23, 95% CI: 1.02–1.47, P = 0.03). On multivariable analysis, which adjusted for the effect of established clinicopathologic features, high DRR remained significantly associated with both OS (HR: 1.26, 95% CI: 1.04-1.52, P = 0.02) and CSS (HR: 1.26, 95% CI: 1.05–1.53, P = 0.01). The addition of DRR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index = 0.633 vs. C-index = 0.629). On decision curve analysis, the inclusion of DRR did not improve the net-benefit beyond that obtained by established subgroup analyses stratified by IMDC risk groups, type of systemic therapy, body mass index and sarcomatoid features, did not reveal any prognostic value to DRR.ConclusionDespite the statistically significant association between DRR and OS as well as CSS in mRCC patients treated with CN, DRR does not seem to add any further prognostic value beyond that obtained by currently available features.     

Evaluation of the platelet-to-lymphocyte ratio as a prognostic indicator in a European cohort of patients with prostate cancer treated with radiotherapy

ObjectivesRecent evidence suggests that the presence of a systemic inflammatory response plays an important role in the progression of several solid tumors. The platelet-to-lymphocyte ratio (PLR) has been proposed as an easily assessable marker of systemic inflammation and has been shown to represent a prognostic marker in different cancer entities. To evaluate the prognostic value of the PLR in prostate cancer, we performed the present study.Methods and materialsData from 374 consecutive patients with prostate cancer, treated with 3D conformal radiotherapy from 1999 to 2007, were analyzed. Distant metastases–free survival (MFS), cancer-specific survival (CSS), overall survival (OS), biochemical disease–free survival, and time to salvage systemic therapy were assessed using the Kaplan-Meier method. Cox proportional hazards analysis was performed to calculate hazard ratio (HR) and 95% CI. Multivariate Cox regression analysis was performed to adjust for other covariates.ResultsUsing receiver operating characteristics analysis, the optimal cutoff level for the PLR was 190. Kaplan-Meier analyses revealed that PLR≥190 was a prognostic factor for decreased MFS (P = 0.004), CSS (P = 0.004), and OS (P = 0.024) whereas a significant association of an elevated PLR with biochemical disease–free survival (P = 0.740) and time to salvage systemic therapy (P = 0.063) was not detected. In multivariate analysis, an increased PLR remained a significant prognostic factor for poor MFS (HR = 2.24, 95% CI: 1.06–4.76, P = 0.036), CSS (HR = 3.99, 95% CI: 1.19–13.4, P = 0.025), and OS (HR = 1.87, 95% CI: 1.02–3.42, P = 0.044).ConclusionsOur findings indicate that the PLR may predict prognosis in patients with prostate cancer and may contribute to future individual risk assessment in them.     

Effect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy

ObjectiveTo evaluate the prognostic effect of concomitant variant histology (CVH) on survival outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy.Materials and methodsData on 417 patients with UTUC treated with radical nephroureterectomy without preoperative adjuvant therapy were retrospectively reviewed with a focus on CVH. Clinicopathological features and prognostic factors were compared between patients with pure UTUC and patients with UTUC with CVH. The primary end points were cancer-specific survival (CSS), disease recurrence-free survival (DFS), and overall survival (OS).ResultsUTUC with CVH was present in 90 (21.6%) of 417 patients. At a median follow-up of 26 months, 153 (36.7%) had died of UTUC, 161 (38.6%) had experienced a relapse, and 176 (42.2%) had died of other causes. UTUC with CVH was significantly associated with advanced tumor stage, high tumor grade, tumor diameter, lymphovascular invasion, lymph node metastasis, positive surgical margins, and tumor architecture compared with pure UTUC (all P<0.01). The estimated 5-year CSS, DFS, and OS rates were 64.9%, 61.1%, and 62.1%, respectively, in the pure UTUC group, compared with 36.3%, 34.3%, and 26.5%, respectively, in the UTUC with CVH group (P<0.001). Multivariate analysis demonstrated that CVH was an independent predictor of CSS (hazard ratio [HR] = 1.594; 95% CI: 1.125–2.259; P = 0.009), DFS (HR = 1.549; 95% CI: 1.077–2.152; P = 0.017), and OS (HR = 1.685; 95% CI: 1.212–2.343; P = 0.002).ConclusionsApproximately one-fifth of the specimens of patients with UTUC were observed to exhibit CVH. CVH was an independent prognostic factor for CSS, DFS, and OS in patients with UTUC on both univariate and multivariate analyses. Genitourinary pathologists should look for potential CVH components in UTUC specimens and report this in routine pathological practice. The presence of CVH should identify patients as candidates for consultation regarding early adjuvant therapy and intensive surveillance protocols.     

Impact of preoperative serum albumin-globulin ratio on disease outcome after radical cystectomy for urothelial carcinoma of the bladder

IntroductionThe Albumin-Globulin Ratio (AGR; albumin/total protein ? albumin) has been associated with oncological outcome in various malignancies. However, its role in urothelial carcinoma of the bladder (UCB) has not been clearly established. In this study, we assessed the association of preoperative AGR (pAGR) with survival in patients who underwent radical cystectomy (RC) for UCB.Material and MethodsWe conducted a retrospective analysis of an established multicenter database of 4.335 patients who were treated with RC for UCB. The cohort was divided into 2 groups according to the pAGR status. Binominal logistic regression as well as uni- and multivariable Cox regression analyses were used. The predictive value of the models was assessed by calculating receiver operating characteristics curves and concordance-indices (C-Index). The additional clinical value was assessed using the decision curve analysis (DCA).ResultsOverall, 1.670 patients (38.5%) had a low pAGR. On multivariable logistic regression analyses, low pAGR was associated with an increased risk of ≥pT3 disease at RC (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.01–1.31, P= 0.04). On multivariable Cox regression analyses, low pAGR remained associated with worse recurrence-free survival (RFS, HR 1.24, 95% CI 1.1–1.37, P< 0.001), cancer-specific survival (CSS, HR 1.23, 95% CI 1.1–1.38, P< 0.001) and overall survival (OS, HR 1.17, 95% CI 1.07–1.28, P< 0.001). The addition of pAGR to multiple prognostic models that were respectively fitted for clinical and postoperative variables did not improve the predictive accuracy.ConclusionpAGR status is an independent predictor of ≥pT3 disease, therefore it could help identify patients who have a higher likelihood to benefit from neoadjuvant systemic therapy. While pAGR was independently associated with RFS, CSS, and OS, it did not improve the predictive accuracy and clinical value beyond obtained by information already available. The predictive value of this biomarker in the age of immunotherapy needs further evaluation.     

Prognostic significance of serum lactate dehydrogenase in patients undergoing radical cystectomy for bladder cancer

BackgroundTo investigate the prognostic significance of preoperative serum lactate dehydrogenase (LDH) in patients undergoing radical cystectomy for bladder cancer (BCa).Patients and methodsA cohort of 263 patients undergoing open or laparoscopic radical cystectomy between 2011 and 2016 was studied. Baseline characteristics, hematological variables, follow-up data were collected. Kaplan-Meier curves and Cox proportional hazard regression model were applied to assess the relationship between LDH and overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS).ResultsAfter a median 34.2 (22.9–45.8) months follow-up, all-cause death, cancer-specific death, and disease recurrence occurred in 66 patients, 50 patients, and 91 patients. The elevation of serum LDH was associated with several unfavorable parameters, including advanced age, continent cutaneous urinary diversion, increased neutrophil-to-lymphocyte ratio, decreased lymphocyte-to-monocyte ratio. Patients with a higher serum LDH (> 220 U/L) had a worse OS (P < 0.001), CSS (P < 0.001) and DFS (P < 0.001). Multivariate Cox analysis suggested that elevated LDH was an independent predictor for OS (hazard ratio [HR]: 3.113, 95% confidence interval [CI]: 1.524–6.358; P = 0.002), CSS (HR: 4.564, 95% CI: 2.008–10.373; P < 0.001), DFS (HR: 2.051, 95% CI: 1.125–3.739; P = 0.019). Medical history of diabetes, high pT stage, and positive lymph node also were adverse predictors for oncological outcomes of BCa patients in multivariate analysis.ConclusionsPreoperative serum LDH is an independent prognostic biomarker for OS, CSS, and DFS in patients undergoing radical cystectomy for BCa, which can be incorporated into prognostic models.     

Prognostic impact of somatostatin receptor expression in advanced bladder cancer

Introduction and objectivesSomatostatin receptors (SSTR) recently have been identified as potential targets for treatment of solid tumors. Furthermore, they have been shown to be of high relevance for tumor biology and prognosis in various types of cancer. However, there is a lack of clinical data for SSTR in bladder cancer (BC). Aim of this study was to determine the expression of all relevant somatostatin receptor subtypes in benign urothelium and tumor tissue of patients with muscle invasive BC. Furthermore, their potential role as prognostic factor for cancer-specific survival (CSS) and overall survival (OS) was evaluated.MethodsThe collective included BC and benign urothelium tissue of 103 patients (Median age 69; range 32–84, 79 male, 24 female) who underwent a radical cystectomy. A tissue microarray with subsequent immunohistochemical staining was used to assess membranous expression of SSTR1–5. Results were correlated to clinical and histopathological data as well as CSS and OS.ResultsExpressions of SSTR1-4 were significantly decreased in BC compared to benign urothelium (P < 0.002 each), whereas SSTR5 expression was increased (P = 0.0017). Expression of SSTR1 was associated with organ–confined disease (≤pT2) (P = 0.0477). No correlation between SSTR1-5 expression and N- and M-stage was observed. Univariate analyses showed a significantly longer CSS and OS in patients with high expression of SSTR3 (P = 0.0316 and 0.0044). Multivariate analyses confirmed SSTR3 expression as independent marker of improved CSS and OS (P = 0.0324 and 0.0076).ConclusionsThe majority of somatostatin receptor subtypes exhibit decreased expression in BC compared to benign bladder tissue. Expression of SSTR3 is an indicator for favorable prognosis in patients with muscle-invasive BC. These results support preclinical investigations using somatostatin receptor analogues such as octreotide to influence BC growth.     

Prognostic effect of preoperative serum albumin to globulin ratio in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

BackgroundAccurate identification of ideal candidates for cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is an unmet need. We tested the association between preoperative value of systemic albumin to globulin ratio (AGR) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.MethodsmRCC patients treated with CN were included. The overall population was therefore divided into two AGR groups using cut-off of 1.43 (low, <1.43 vs. high, ≥1.43). Univariable and multivariable Cox regression analyses tested the association between AGR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel’s concordance index (C-index). The clinical value of the AGR was evaluated with decision curve analysis (DCA).ResultsAmong 613 mRCC patients, 159 (26%) patients had an AGR <1.43. Median follow-up was 31 (IQR: 16–58) months. On univariable analysis, low preoperative serum AGR was significantly associated with both OS (HR: 1.55, 95% CI: 1.26–1.89, P<0.001) and CSS (HR: 1.55, 95% CI: 1.27–1.90, P<0.001). On multivariable analysis, AGR <1.43 was associated with worse OS (HR: 1.51, 95% CI: 1.23–1.85, P<0.001) and CSS (HR: 1.52, 95% CI: 1.24–1.86, P<0.001). The addition of AGR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index=0.640 vs. C-index=0.629). On DCA, the inclusion of AGR marginally improved the net benefit of the prognostic model. Low AGR remained independently associated with OS and CSS in the IMDC intermediate risk group (HR: 1.52, 95% CI: 1.16–1.99, P=0.002).ConclusionsIn our study, low AGR before CN was associated with worse OS and CSS, particularly in intermediate risk patients.     

Increased preoperative levels of plasma fibrinogen and d dimer in patients with renal cell carcinoma is associated with poor survival and adverse tumor characteristics

Background and objectiveThe relationship between renal cell carcinoma (RCC) and coagulation/fibrinolysis system has been described in several studies. The aim of this study was to investigate the role of 4 different coagulation/fibrinolysis factors on the prediction of histopathologic and survival prognosis in patients with RCC.Patients and methodsData from 128 patients who underwent surgical intervention between March 2006 and January 2011 for RCC were evaluated in this prospective study. Blood samples were collected from all patients on the morning of the operation to measure the plasma fibrinogen, d-dimer, coagulation factor VII, and antithrombin 3 levels. The relationships of these factors in the demographic, clinical, and histopathologic outcomes were analyzed using the Student t, Mann-Whitney U, Kruskal-Wallis, and one-way analysis of variance tests. Receiver operating curve analyses were performed to determine the optimal cutoff level for fibrinogen and d dimer, both of which had a strong relation with the clinical and histopathologic parameters. Disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using the Kaplan-Meier method. Multivariate Cox regression analyses (forward stepwise logistic regression) were performed to examine the independent prognostic values on survival outcomes.ResultsIncreased plasma fibrinogen and d-dimer levels were associated with tumor size (P = 0.004 and 0.106), nuclear grade (P<0.001 and<0.001), TNM category (P<0.001 and 0.029), and metastasis (P<0.001 and 0.032). Both increased plasma fibrinogen and d-dimer levels predicted decreased DFS (P = 0.027 and 0.04), CSS (P = 0.007 and 0.043), and OS (P = 0.014 and 0.001) rates based on Kaplan-Meier analyses. Furthermore, multivariate analyses demonstrated that fibrinogen independently predicted poor DFS (hazard ratio [HR] = 2.52; 95% CI: 1.04–6.31; P = 0.029) and CSS (HR = 3.89; 95% CI: 1.13–13.40; P = 0.032), whereas d dimer had negative independent prognostic value on OS (HR = 4.01; 95% CI: 1.54–10.50; P = 0.005).ConclusionsIncreased plasma fibrinogen levels accurately predict poor histopathologic and survival outcomes and may be an effective independent prognostic factor in patients with RCC. Moreover, d dimer may serve as a copredictive factor in conjunction with fibrinogen.     

High expression of ERBB2 is an independent risk factor for reduced recurrence-free survival in patients with stage T1 non-muscle-invasive bladder cancer

IntroductionMolecular markers associated with breast cancer are assumed to be associated with outcome in non-muscle-invasive bladder cancer (NMIBC).Materials and methodsWe retrospectively investigated the association of the mRNA expression of estrogen receptor 1 (ESR1) and 2 (ESR2), progesterone receptor (PGR), MKI67, and HER2 (ERBB2) with recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) in 80 patients with stage T1 NMIBC.ResultsHigh expression of ESR2 (P = 0.003), ERBB2 (P < 0.001), and MKI67 (P = 0.029) was associated with shorter RFS. Only high ERBB2 was an independent prognostic factor for reduced RFS (HR = 2.98; P = 0.009). When sub stratifying the cohort, high ESR2 was associated with reduced RFS (P < 0.001), CSS (P = 0.037) and OS (P = 0.006) in patients without instillation therapy. High ESR2 was associated with reduced CSS (P = 0.018) and OS (P = 0.029) in females and with shorter RFS in both sexes (males: P = 0.035; females: P = 0.010). Patients with high ERBB2 showed reduced CSS (P = 0.011) and OS (P = 0.042) in females and reduced CSS (P = 0.012) in those without instillation, while RFS was significantly reduced irrespective of sex or instillation.ConclusionHigh mRNA expression of ERBB2 is an independent predictor of reduced RFS in patients with stage T1 NMIBC. High ERBB2 and ESR2 are associated with reduced outcomes, especially in females and patients without instillation therapy.     

Association of intraoperative hypothermia with oncologic outcomes following radical cystectomy

IntroductionIntraoperative hypothermia (IOH) has been suggested to adversely impact outcomes following surgery. The objective of this study was to evaluate the association between IOH and survival following radical cystectomy (RC).MethodsPatients who underwent RC for bladder cancer from 2003 to 2018 were identified in our cystectomy registry. Intraoperative temperatures were extracted from the anesthesia record. IOH was defined as a median intraoperative temperature <36°C, and severe IOH as ≤ 35°C. Time under 36°C was assessed as a continuous variable. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Associations between IOH and outcomes were assessed with multivariable Cox proportional hazards models.ResultsA total of 852 patients were identified, among whom 274 (32%) had IOH. Median follow up among survivors was 4.9 years (IQR 2.4–8.7), during which time 483 patients died, including 343 from bladder cancer. Two-year survival was not significantly different between patients with and without IOH (CSS: 74% vs. 71%, P= 0.31; OS: 68% vs. 67%, P= 0.13). Following multivariable adjustment, neither IOH nor time under 36°C was significantly associated with survival. A total of 37 patients (4.3%) had severe IOH. These patients were observed to have significantly lower 2-year OS (56% vs. 68%, P= 0.005); however, this association did not remain statistically significant after multivariable adjustment (P= 0.92).ConclusionIOH was not independently associated with survival following RC. These data do not support IOH as a prognostic factor for cancer outcomes among patients undergoing RC.     

Clinically node-positive (cN+) urothelial carcinoma of the bladder treated with chemotherapy and radical cystectomy: Clinical outcomes and development of a postoperative risk stratification model

Introduction and objectiveAlthough node-positive (cN+) bladder cancer is considered Stage IV disease, a subset of patients is treated with chemotherapy and consolidative radical cystectomy (RC). We examined the clinical outcomes of such patients and developed a risk prediction model to facilitate risk-stratification and management.MethodsWe identified adult patients with cTany cN1-3 M0 urothelial carcinoma of the bladder treated with chemotherapy followed by RC from 2006 to 2013 in the NCDB. The associations of clinicopathologic features with overall survival (OS) were evaluated using Cox regression, and a simplified risk score was developed.ResultsA total of 491 patients received chemotherapy followed by RC. Median number of lymph nodes removed was 16 (interquartile range 9–25). At RC, 10% of patients were ypT0, and 35% were ypN0. Over a median follow-up of 18.7 months, 160 patients died of any cause. 1-, 5-, and 8-year OS were 69%, 34%, and 29%, respectively. On multivariable analysis, pT stage (hazard ratio [HR] 2.18; P = 0.003 for pT3, HR 2.65; P < 0.001 for pT4 vs. <pT2) and pN stage (HR 1.77; P = 0.02 for pN1; HR 2.58; P < 0.001 for pN2; HR 5.09; P < 0.001 for pN3 vs. pN0) were independently associated with worse OS. A risk score was developed based on pT and pN stages, with 5-year OS of 59%, 24%, and 10% for risk score groups of 0-1, 2, and ≥3 points.ConclusionsSurvival for patients with cN+ bladder cancer treated with chemotherapy and RC is highly variable, ranging from 10% to 59% at 5 years. A risk score can facilitate postoperative risk-stratification and selection of patients for adjuvant therapy.     

Evaluation of lymphovascular invasion as a prognostic predictor of overall survival after radical prostatectomy

ObjectiveTo assess the prognostic ability of lymphovascular invasion (LVI) as a predictor of overall survival (OS).Materials and MethodsWe included 126,682 prostate cancer (CaP) cM0 patients who underwent radical prostatectomy with lymph node dissection between 2010 and 2015, within the National Cancer Database. Patients who received androgen deprivation therapy were included. Patients were divided into four sub-cohorts based on LVI and lymph node invasion (LNI) status: pL₀N₀, pL₁N₀, pL₀N₁, and pL₁N₁. Kaplan-Meier curves estimated OS and Cox-regression analysis tested the relationship between LVI and OS.ResultsMedian (IQR) age and PSA at diagnosis were 62 (57-66) years and 5.7 (4.5-8.9) ng/ml, respectively. Most patients had pT2 stage (68.5%), and pathological Gleason 3+4 (46.7%). 10.0% and 4.0% patients had LVI and LNI, respectively. Median follow-up was 42 months (27-58). At 5-years, OS was 96.5% in pL₀N₀ patients vs 93.1% pL₁N₀ patients vs 93.3% in pL₀N₁ patients vs 86.6% pL₁N₁ patients. LVI was an independent predictor of OS (hazard ratio [HR]:1.28). LVI showed interaction with LNI, as LVI was associated with a higher overall-mortality in patients with LNI (HR:1.66), than in patients without LNI (HR:1.22). (all P<0.0001)ConclusionsOur report highlights the detrimental impact of LVI on OS. Patients with LVI alone fared similarly to patients with LNI alone. Patients with both LVI and LNI had worse OS than those with only LVI or LNI, implying a synergetic detrimental interaction. Our findings demonstrate an important utility that LVI can provide in deciding patients’ prognoses.     

The effect of sex on disease stage and survival after radical cystectomy: a population-based analysis

BackgroundThe increased awareness regarding the sex gap in bladder cancer (BCa) care over the last decade may have resulted in more timely-wise referral patterns and treatment of female patients with BCa. Thus, we tested the association of sex with disease stage at presentation, as well as with cancer-specific mortality (CSM) after radical cystectomy (RC) in a contemporary cohort of patients with nonmetastatic urothelial bladder cancer (UCUB).MethodsWithin the Surveillance, Epidemiology, and End Results database (2004–2016), we identified 14,086 patients (10,879 men and 3,207 women) treated with RC for non-metastatic UCUB. Temporal trend, interaction analyses, logistic regression, cumulative incidence, and competing-risks regression analyses were used.ResultsOverall, 10,879 (77.2%) men and 3,207 (22.8%) women underwent RC between 2004 and 2016. Female gender was an independent predictor of non-organ-confined (NOC) UCUB at RC in multivariable analyses (odds ratio: 1.23; 95% confidence intervals [CI] 1.10–1.38; P < 0.001). While NOC rates in men decreased over time (from 54.8% to 45.7%; P < 0.01), NOC rates in women remained stationary (from 60.6% to 57.3%; P = 0.15) and the excess NOC rate between men and women increased from + 5.8% in 2004 to +11.6% in 2016. Moreover, in multivariable analyses adjusted for other covariates, female gender was an independent predictor of higher CSM after RC in NOC UCUB (HR: 1.14; 95%CI 1.04–1.24; P < 0.01), but not in localized UCUB (P = 0.06).ConclusionIt is worrisome that, while in men the rate of NOC is decreasing, NOC rates in females have not improved over time. Moreover, it is also worrisome that, despite adjustment for both pathological tumor and patient characteristics, female sex remains an adverse prognostic factor for CSM. Reassessment of referral, diagnostic, and treatment patterns aimed at eliminating these sex discrepancies appears warranted.     

Residual CIS after neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer: Implications for neoadjuvant trials

PurposeTo better define surrogate endpoints for neoadjuvant chemotherapy (NAC) trials in patients with muscle-invasive bladder cancer. We compared survival in patients with carcinoma in-situ (CIS) only vs. complete response following NAC and radical cystectomy (RC).Materials and MethodsPatients with cT2-4N0M0 disease treated with NAC and RC between 2001 and 2018 were stratified by response: complete response (CR, pT0N0), partial response (PR, pTaN0, pT1N0+/-CIS), CIS-only (pTisN0), stable disease (SD, pT2N0), or progressive disease (PD, >pT2N0). Primary endpoints were overall survival (OS) and risk of recurrence in patients with CIS-only vs. CR. Multivariable Cox proportional hazards regression model was used for OS and a competing risks proportional hazards model was used for risk of recurrence.ResultsOf 1,406 patients in our institution cohort, 340 patients met inclusion criteria. Kaplan-Meier mean estimates of OS for CR and CIS-only were 108.9 months (95% CI 89.7–127.9) and 125.8 months (95% CI 112.3–139.3), respectively (P = 0.13). Cox proportional hazards model found no difference in OS between patients with PR (HR 1.06, 95% CI 0.33–2.58, P = 0.897) or CIS-only (HR 0.422, 95% CI 0.15–1.18, P = 0.101) when compared to CR. The risk of recurrence was similar between patients with CIS-only (HR 0.73, 95% 0.29–1.84, P = 0.49) and PR (HR 1.32, 95% CI 0.54–3.29, P = 0.54) when compared to CR on competing risks analysis.ConclusionsResidual CIS-only after NAC and RC demonstrated similar survival outcomes when compared to patients with pathologic CR. Further study in large multi-institutional cohorts may further validate CIS-only as an additional surrogate endpoint after NAC and may inform future trials.     

Assessing pentafecta achievement after robot-assisted radical cystectomy and its association with surgical experience: Results from a high-volume institution

ObjectivesRadical cystectomy (RC) represents the gold standard treatment for high-risk bladder cancer. Despite evidence suggesting that surgical experience correlates with perioperative and oncologic outcomes of robot-assisted RC (RARC), validated tools to assess its quality objectively are lacking. We aimed to evaluate the impact of RC-Pentafecta (absence of early major complications, absence of urinary diversion related sequelae at ≤12 months, absence of soft tissue surgical margins, ≥16 lymph nodes at final pathology and absence of clinical recurrence at ≤12 months) on oncological outcomes and the role of surgical experience on its achievement.Materials and methodsWe retrospectively evaluated 366 patients undergoing RARC with intracorporeal urinary diversion in a single tertiary centre with a minimum of 1 year follow-up. Surgeries were performed using the DaVinci Xi system according to a previously described technique. Kaplan-Meier curves were used to investigate 5-years overall survival and cancer specific mortality-free survival (CSS) according to RC-Pentafecta achievement. Multivariable Cox's regressions were performed to evaluate the impact of RC-Pentafecta on overall mortality. Multivariable logistic regressions were performed to explore the effect of surgical experience on RC-pentafecta achievement. Locally weighted scatterplot smoother function was used to graphically explore this relationship.ResultsPatients achieving RC-Pentafecta showed higher 5-year overall survival (71.8% vs. 59.6%, P < 0.001) and CSS (84% vs. 71%, P < 0.001) when compared with patients not achieving it. At multivariable Cox's regression, RC-Pentafecta achievement (HR 0.57, P = 0.03), positive surgical margins (HR 2.48, P = 0.002), pN+ (HR 2.23, P = 0.002), pT≥3 (HR 1.71, P = 0.04) and current smoking status (HR 2.4, P = 0.006) were significant predictors of overall mortality. At multivariable logistic regression surgical experience (OR 1.2, P < 0.001), age (OR 0.93, P = 0.04), previous prostate surgery (OR 0.7, P = 0.02) and pT≥3 (OR 0.8, P = 0.03) were independent predictors of RC-Pentafecta achievement. A linear relationship between surgical experience and RC-Pentafecta achievement, without reaching a plateau, was observed.ConclusionsRC-Pentafecta is a valuable tool to assess surgical quality of RARC and the experience of the center where the surgery is performed and may be used to identify “referral” centers for treatment of high-risk bladder cancer.     

The prognostic value of the urokinase-plasminogen activator system (uPA) in bladder cancer patients treated with radical cystectomy (RC)

PurposeUrokinase-plasminogen activator (uPA), its receptor (uPAR), and the plasmin-activator inhibitor type 1 (PAI-1) have been associated with oncologic outcomes in various malignancies and could help identify bladder cancer (BC) patients treated with radical cystectomy (RC) who are likely to benefit from intensification of therapy to prevent disease progression. Our aim was to assess the value of uPA, uPAR, and PAI-1 for prognosticating survival outcomes of patients treated with RC for BC.Materials and methodsTumor specimens from 272 consecutive patients treated with RC for advanced BC were assessed with immunohistochemical staining for uPA, uPAR, and PAI-1. Overexpression was assessed by pathological image analysis. Kaplan-Meier estimates and multivariable Cox-regression were used to analyze survival. Harrell's C-index was used to assess for clinical impact of the uPA system.ResultsuPA, uPAR, and PAI-1 were overexpressed in 48.2%, 51.1%, and 52.2% of patients, respectively. uPA overexpression was associated with lymphovascular invasion (P = 0.034) and nodal status (P = 0.013); PAI-1 overexpression was associated with primary muscle-invasive BC (P = 0.015) and lymphovascular invasion (P = 0.024). uPA, uPAR, and the number of overexpressed markers were all 3 significantly associated with shorter overall recurrence-free-, distant recurrence-free-, and cancer-specific survival. In multivariable analyses, uPA overexpression remained associated with shorter recurrence-free survival (hazard ratio [HR] = 1.79; P = 0.036) in the entire cohort, in patients without lymph node metastasis (HR = 1.98; P = 0.018) and those with nonorgan-confined disease (HR = 1.98; P = 0.022). uPAR overexpression was associated with shorter recurrence-free survival in patients without lymph node metastasis (HR = 2.01; P = 0.021) and those with organ-confined disease (HR = 4.11; P = 0.037).ConclusionMembers of the uPA system are associated with features of biologically aggressive BC and oncologic outcomes. However, their value beyond currently available information remains limited.     

Lymph node count at radical cystectomy does not influence long-term survival if surgeons adhere to a standardized template

IntroductionMultiple bladder cancer studies report that the number of removed lymph nodes (lymph node count [LNC]) at radical cystectomy (RC) is positively associated with survival. Although these reports suggest that LNC can be used as a proxy for surgical quality, all studies used variable or inconsistent pelvic lymph node dissection (PLND) templates. We therefore wished to establish whether LNC at RC influences survival if surgeons adhere to a standardized PLND template.Materials and methodsWe included 274 patients who underwent RC from January 2005 until December 2012. All RCs were performed in either one of 2 hospitals (hospital A or B) by the same 4 urologists (all from hospital A) and a standardized PLND template was applied. PLND specimens were processed by 2 independent pathology departments (hospital A and B). We used Cox regression analysis to investigate the prognostic value of LNC adjusted for patient characteristics. We also compared LNC between hospitals and surgeons and investigated the effect of both the variables on overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS).ResultsMedian LNC was 17 (interquartile range = 12). At a median follow-up of 64.3 months, there was no association between LNC and OS (P = 0.328), CSS (P = 0.645), or DFS (P = 0.450). Median LNC was higher in hospital B than in hospital A (20.0 vs. 16.0, P = 0.003). Median LNC varied significantly among surgeons (12–20, P<0.001). Neither the hospital of surgery nor the surgeon performing PLND influenced OS (P = 0.771 and P = 0.982, respectively), CSS (P = 0.310 and P = 0.691, respectively), or DFS (P = 0.256 and P = 0.296, respectively).ConclusionIf surgeons adhere to a standardized template, LNC at RC does not affect long-term survival.     

Prognostic impact of tumor-associated immune cell infiltrates at radical cystectomy for bladder cancer

ObjectivesTo assess whether the presence and location of tumor-associated immune cell infiltrates (TAIC) on histological slides obtained from cystectomy specimens impacts on oncological outcomes of patients with bladder cancer (BC).Material and methodsA total of 320 consecutive patients staged with cM0 bladder cancer underwent radical cystectomy (RC) between 2004 and 2013. The presence of TAIC (either located peritumorally [PIC] and/or intratumorally [IIC]) on histological slides was retrospectively assessed and correlated with outcomes. Kaplan–Meier analyses were used to estimate the impact of TAIC on recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS). Multivariable Cox-regression analysis was carried out to evaluate risk factors of recurrence. The median follow-up was 37 months (IQR: 10–55).ResultsOf the 320 patients, 42 (13.1%) exhibited IIC, 141 (44.1%) PIC and 137 (42.8%) no TAIC in the cystectomy specimens. Absence of TAIC was associated with higher ECOG performance status (P = 0.042), histologically advanced tumor stage (≥pT3a; P < 0.001), lymph node tumor involvement (pN+; P = 0.022), positive soft tissue surgical margins (P = 0.006), lymphovascular invasion (P < 0.001), and elevated serum C-reactive protein levels (P < 0.001). The rate of never smokers was significantly higher in the IIC-group (64.3%) compared to the PIC-group (39.7%, P = 0.007) and those without TAIC (35.8%, P = 0.001). The 3-year RFS/CSS/OS was 73.9%/88.5%/76.7% for patients with IIC, 69.4%/85.2%/70.1% for PIC and 47.6%/68.5%/56.1% for patients without TAIC (P < 0.001/<0.001/0.001 for TAIC vs. no TAIC). In multivariable analysis, adjusted for all significant parameters of univariable analysis, histologically advanced tumor stage (P = 0.003), node-positive disease (P = 0.002), and the absence of TAIC (P = 0.035) were independent prognosticators for recurrence.ConclusionsIn this analysis, the presence and location of TAIC in cystectomy specimens was a strong prognosticator for RFS after RC. This finding suggests that the capability of immune cells to migrate into the tumor at the time of RC is prognostically important in invasive bladder cancer.