Atiqullah Aziz

Prediction of 90-day Mortality After Radical Cystectomy for Bladder Cancer in a Prospective European Multicenter Cohort

BACKGROUND Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. OBJECTIVE To validate the performance of the Isbarn nomogram incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. DESIGN, SETTING, AND PARTICIPANTS Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. INTERVENTION RC for BCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics-derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. RESULTS AND LIMITATIONS The 30-, 60-, and 90-d mortality rates in the development cohort (n=597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio [OR]:1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p<0.05) as independent predictors of 90-d mortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. CONCLUSIONS The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. PATIENT SUMMARY The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates.

Predictors of cancer-specific mortality after disease recurrence following radical cystectomy.

Study Type – Therapy (case series)

Prediction of Intravesical Recurrence After Radical Nephroureterectomy: Development of a Clinical Decision-making Tool

BACKGROUND Intravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. OBJECTIVE The aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. INTERVENTIONS RNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Univariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. RESULTS AND LIMITATIONS With a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85% ± 1%, 78% ± 1%, 68% ± 1%, and 47% ± 2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values ≤ 0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study. CONCLUSIONS Intravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU.

Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder.

BACKGROUND Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. OBJECTIVES The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). METHODS This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79). RESULTS Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. CONCLUSIONS After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.

Impact of Preoperative Anemia on Oncologic Outcomes of Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

PURPOSE We evaluated the impact of preoperative anemia on oncologic outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. MATERIALS AND METHODS A total of 282 patients with upper tract urothelial carcinoma underwent radical nephroureterectomy. Preoperatively measured hemoglobin values were stratified into normal and anemia based on the WHO classification of 13 gm/dl or less and 12 or less considered anemia in males and females, respectively. We performed sensitivity analysis based on contemporary anemia classifications adjusted for the impact of age, gender and race with anemia considered a hemoglobin value of 13.7 gm/dl or less and 13.2 or less in white males younger than 60 and 60 years old or older, respectively, and 12.2 gm/dl or less in white females of all ages. Univariable and multivariable Cox regression analyses were done to assess the effects of anemia on oncologic outcomes. RESULTS Median preoperative hemoglobin was 13.2 gm/dl (IQR 11.7, 14.3). A total of 112 patients (39.7%) were anemic by the WHO classification vs 129 (45.7%) by the contemporary classification. Anemia was associated with lymph node metastasis, lymphovascular invasion, sessile tumor architecture, tumor necrosis, advanced age and a higher ECOG (Eastern Cooperative Oncology Group) performance score using the WHO and/or the contemporary definition (p ≤0.044). At a median 30-month followup anemia was associated with decreased recurrence-free (p ≤0.008) and cancer specific (p <0.001) survival on Kaplan-Meier analyses. On multivariable analysis adjusted for standard clinicopathological factors anemia remained an independent predictor of disease recurrence (HR 1.76, 95% CI 1.17-2.63 and 1.89, 95% CI 1.26-2.86) and cancer specific mortality (HR 1.88, 95% CI 1.15-3.08 and 2.04, 95% CI 1.21-3.45) by the WHO and contemporary classifications, respectively. CONCLUSIONS Preoperative anemia is an independent predictor of disease recurrence and cancer specific mortality. It is associated with aggressive tumor features in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. Hemoglobin is a promising marker for patient counseling and risk stratification for additional treatment decision making.

Prognostic Value of Perinodal Lymphovascular Invasion Following Radical Cystectomy for Lymph Node-positive Urothelial Carcinoma

BACKGROUND Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined. OBJECTIVE To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival. DESIGN, SETTING, AND PARTICIPANTS A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%). INTERVENTION Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11-38). RESULTS AND LIMITATIONS Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p<0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p=0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p=0.856), and the incremental accuracy of prediction is of uncertain clinical value. CONCLUSIONS We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.

Body mass index has no impact on sperm quality but on reproductive hormones levels.

The influence of overweight and obesity on sperm quality and reproductive hormone levels is under discussion. The aim of the present retrospective study was to evaluate the influence of body mass index (BMI) on sperm quality and reproductive hormones. We analysed semen samples and serum levels of FSH, LH, T and PRL of a total of 2110 men attending our andrology unit from 1994 to 2010 due to infertility work‐up. Patients were stratified according to their BMI in four groups. Main outcome measures were sperm motility, morphology and concentration. Serum levels of FSH, LH, T and PRL were evaluated as well. No statistically significant difference was found for sperm quality and BMI between patients categorised according to the four BMI levels. T (P < 0.001) and LH (P = 0.006) significantly differed between the four groups. In multivariable analysis, BMI did not have significantly independent influence on all assessed sperm quality parameters, whereas BMI significantly influenced hormone values for LH (P = 0.001), T (P = <0.001) and PRL (P = 0.044). We therefore conclude that BMI has no significant impact on sperm quality parameters. However, serum levels of LH, T and PRL were significantly influenced by BMI.

Preoperative C-reactive protein in the serum: a prognostic biomarker for upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

Objective: To investigate the impact of preoperative serum C-reactive protein (CRP) on clinicopathological features and prognosis in patients with upper tract urothelial cancer (UTUC) after radical nephroureterectomy (RNU). Patients andMethods: Data of 265 patients from three German centers who underwent RNU for UTUC without neoadjuvant chemotherapy between 1990 and 2012 were evaluated. Mean follow-up was 37 months (interquartile range 9-48). CRP was analyzed as a categorical and continuous variable for the prediction of recurrence-free survival (RFS), disease-specific survival (DSS) and all-cause survival (ACS) using uni- and multivariate Cox regression analyses. Results: The optimal cutoff for CRP was calculated by the Youden index at 0.90 mg/dl. Elevated CRP was significantly associated with pT3/4 and pN+ in a preoperative model including age, gender, tumor multifocality, tumor localization and the Eastern Cooperative Oncology Group Performance Status. In a multivariable Cox regression model adjusted for features significant in univariable analysis, categorized and continuous CRP levels were both independent predictors for RFS [hazard ratio (HR) 1.18, p = 0.050; HR 1.03, p = 0.012] and DSS (HR 1.61, p = 0.026; HR 1.06, p = 0.001). Continuous CRP was an independent predictor for ACS (HR 1.05, p = 0.036). Conclusions: Elevated preoperative CRP is significantly associated with aggressive tumor biology and an independent predictor for poor survival after RNU. Preoperative serum CRP represents an easily obtainable and cost-effective marker in UTUC and may help in counseling patients with regard to operative management and/or adjuvant or neoadjuvant therapies.

The Charlson Comorbidity Index Predicts Survival after Disease Recurrence in Patients following Radical Cystectomy for Urothelial Carcinoma of the Bladder

Objective: To identify prognostic clinical and histopathological parameters, including comorbidity indices at the time of radical cystectomy (RC), for overall survival (OS) after recurrence following RC for urothelial carcinoma of the bladder (UCB). Materials and Methods: A retrospective multicenter study was carried out in 555 unselected consecutive patients who underwent RC with pelvic lymph node dissection for UCB from 2000 to 2010. A total of 227 patients with recurrence comprised our study group. Cox proportional hazards regression models were calculated with established variables to assess their independent influence on OS after recurrence. Results: The median time from RC to recurrence and the median OS after recurrence was 10.9 and 5.4 months, respectively. Neither the time to recurrence nor the type of recurrence (systematic vs. local) was predictive of the OS. In contrast, age (hazard ratio (HR) 1.53, p = 0.011), lymph node metastasis (HR 1.56, p = 0.007), and positive surgical margins (HR 1.53, p = 0.046) significantly affected the OS after disease recurrence. In addition, the dichotomized Charlson comorbidity index (CCI; dichotomized into >2 vs. 0-2) was the only comorbidity score with an independent prediction of OS (HR 1.41, p = 0.033). We observed a significant gain in the base models predictive accuracy, i.e. from 68.4 to 70.3% (p < 0.001), after inclusion of the dichotomized CCI. Conclusions: We present the first outcome study of comorbidity indices used as predictors of OS after disease recurrence in patients undergoing RC for UCB. The CCI at the time of RC had no significant influence on the time to recurrence but represented an independent predictor of OS after disease recurrence.

The Use of Neoadjuvant Chemotherapy in Patients With Urothelial Carcinoma of the Bladder: Current Practice Among Clinicians

Micro‐Abstract Neoadjuvant chemotherapy before radical cystectomy is recommended in patients with bladder cancer in clinical stages T2‐T4a, cN0M0. We analyzed the frequency and current practice of neoadjuvant chemotherapy in 679 patients using uni‐ and multivariable regression analyses and using a questionnaire. We found a great discrepancy between guideline recommendations and practice patterns, despite medical indication and interdisciplinary tumor board discussion. Introduction: Guidelines recommend neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in patients with urothelial carcinoma of the bladder in clinical stages T2‐T4a, cN0M0. We examined the frequency and current practice of NAC and sought to identify predictors for the use of NAC in a prospective contemporary cohort. Materials and Methods: We analyzed prospective data from 679 patients in the PROMETRICS (PROspective MulticEnTer RadIcal Cystectomy Series 2011) database. All patients underwent RC in 2011. Uni‐ and multivariable regression analyses identified predictors of NAC application. Furthermore, a questionnaire was used to evaluate the practice patterns of NAC at the PROMETRICS centers. Results: A total of 235 patients (35%) were included in the analysis. Only 15 patients (2.2%) received NAC before RC. Younger age (< 70 years; P = .035), lower case volume of the center (< 30 RC/year; P < .001), and advanced tumor stage (≥ cT3; P = .038) were identified as predictors for NAC. Of the 200 urologists who replied to the questionnaire, 69% (n = 125) declared tumor stage cT3‐4 a/o N1M0 to be the best indication for NAC application, although 45% of the urologists stated that they would not perform NAC despite recommendations. The decision for NAC was made by the individual urologist in 69% of cases, and only 29% reported that all cases were discussed in an interdisciplinary tumor board. Conclusion: NAC was rarely applied in the present cohort. We observed a discrepancy between guideline recommendations and practice patterns, despite medical indication and pre‐therapeutic interdisciplinary discussion. The potential benefit of NAC within a multimodal approach seems to be neglected by many urologists.