S.F. Shariat

Contemporary 90-day mortality rates after radical cystectomy in the elderly.

INTRODUCTION Existing radical cystectomy (RC) perioperative mortality estimates may underestimate the contemporary rates due to more advanced age, more baseline comorbidities and potentially broader inclusion criteria for RC, relative to past criteria. METHODS Within the most recent Surveillance, Epidemiology, and End Results (SEER)-Medicare database we identified clinically non-metastatic, muscle-invasive (T2-T4a) urothelial carcinoma of the urinary bladder (UCUB) patients, who underwent RC between 1991 and 2009. Mortality at 30- and 90-day after RC was quantified. Multivariable logistic regression analyses tested predictors of 90-day mortality. RESULTS Within 5207 assessable RC patients 30- and 90-day mortality rates were 5.2 and 10.6%, respectively. According to age 65-69, 70-79 and ≥ 80 years, 90-day mortality rates were 6.4, 10.1 and 14.8% (p < 0.001). Additionally, 90-day mortality rates increased with increasing Charlson Comorbidity Index (CCI, 0, 1, 2 and ≥ 3): 6.3, 10.3, 12.6 and 15.9% (p < 0.001). 90-day mortality rate in unmarried patients was 13.0 vs. 9.3% in married individuals (p < 0.001). In multivariable logistic regression analyses, advanced age, higher CCI, low socioeconomic status, unmarried status and non organ-confined stage were independent predictors of 90-day mortality (all p < 0.05). CONCLUSIONS The contemporary SEER-Medicare derived 90-day mortality rates are substantially higher than previously reported estimates from centers of excellence, and even exceed previous SEER reports. More advanced age, higher CCI score, and other patient characteristics that distinguish the current population from others account for these differences.

Utility and limitations of 3-Tesla diffusion-weighted magnetic resonance imaging for differentiation of renal tumors

OBJECTIVE To investigate utility and limitations of 3-Tesla diffusion-weighted (DW) magnetic resonance imaging (MRI) for differentiation of benign versus malignant renal lesions and renal cell carcinoma (RCC) subtypes. MATERIALS AND METHODS Sixty patients with 71 renal lesions underwent 3 Tesla DW-MRI of the kidney before diagnostic tissue confirmation. The images were retrospectively evaluated blinded to histology. Single-shot echo-planar imaging was used as the DW imaging technique. Apparent diffusion coefficient (ADC) values were measured and compared with histopathological characteristics. RESULTS There were 54 malignant and 17 benign lesions, 46 lesions being small renal masses ≤ 4 cm. Papillary RCC lesions had lower ADC values (p=0.029) than other RCC subtypes (clear cell or chromophobe). Diagnostic accuracy of DW-MRI for differentiation of papillary from non-papillary RCC was 70.3% resulting in a sensitivity and specificity of 64.3% (95% CI, 35.1-87.2) and 77.1 (95% CI, 59.9-89.6%). Accuracy increased to 83.7% in small renal masses (≤ 4 cm diameter) and sensitivity and specificity were 75.0% and 88.5%, respectively. The ADC values did not differ significantly between benign and malignant renal lesions (p=0.45). CONCLUSIONS DW-MRI seems to distinguish between papillary and other subtypes of RCCs especially in small renal masses but could not differentiate between benign and malignant renal lesions. Therefore, the use of DW-MRI for preoperative differentiation of renal lesions is limited.

Updated assessment of neoblader utilization and morbidity according to urinary diversion after radical cystectomy: A contemporary US-population-based cohort

BACKGROUND In this paper, we examine contemporary utilization rates and determinants of neobladder (NB) after radical cystectomy (RC) relative to ileal conduit (IC), as well as provide an updated assessment of postoperative morbidity and mortality between NB and IC. METHODS Relying on the Nationwide Inpatient Sample (NIS), we abstracted patients who underwent RC between 2000 and 2010. Subsequently, NB and IC recipients were identified. Use of NB was assessed after accounting for case-mix. Propensity-based matched analyses were used to account for treatment selection biases. Generalized linear regression analyses focused on intra- and postoperative complications, prolonged length of stay, blood transfusions and in-hospital mortality. RESULTS The utilization rate of NB was 6.9% in 2000 and 9.1% in 2010 (p < 0.001). Younger, healthier, privately-insured and wealthier male individuals were more likely to receive a NB. High-volume hospitals were more likely to offer NB. In the post-propensity matched cohort, urinary diversion type failed to be significantly associated with the examined endpoints, except for intra- and postoperative complications (IC vs. NB odds ratio [OR]: 1.15, p = 0.04). INTERPRETATION Despite comparable morbidity and mortality odds between NB and IC, as of the most contemporary year of the study (2010), IC remains the preferred urinary diversion type. Several sociodemographic factors were associated with NB.

Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma.

Background:Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC).Methods:Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months.Results:Median pretherapeutic serum GGT level was 25 U l−1. Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l−1 was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l−1), normal high (17.5 to <34.5 U l−1), elevated (34.5 to <181.5 U l−1), and highly elevated (⩾181.5 U l−1). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit.Conclusions:Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design.

Determinants of long-term survival of patients with locally advanced prostate cancer: the role of extensive pelvic lymph node dissection

Background:The therapeutic effect of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) due to prostate cancer (PCa) is still under debate. We aimed at assessing the impact of more extensive PLND on cancer-specific mortality (CSM) in patients treated with surgery for locally advanced PCa.Methods:We examined data of 1586 pT3-T4 PCa patients treated with RP and extended PLND between 1987 and 2012 at a tertiary referral care center. Univariable and multivariable Cox regression analyses tested the relationship between the number of nodes removed and CSM rate, after adjusting for potential confounders. Survival estimates were based on the multivariable models.Results:The average number of nodes removed was 19 (median: 17; interquartile range: 11–23). Mean and median follow-up were 80 and 72 months, respectively. At multivariable analyses, Gleason score 8–10 (hazard ratio (HR): 2.5) and a higher number of positive nodes (HR: 1.06) were independently associated with higher CSM rate (all P<0.05). Conversely, higher number of removed LNs (HR: 0.94) and adjuvant radiotherapy (HR: 0.54) were independent predictors of lower CSM rates (all P⩽0.03).Conclusions:In pT3-T4 PCa patients, removal of a higher number of LNs during RP was associated with higher cancer-specific survival rates. This supports the role of more extensive PLNDs in this patient group. Further prospective studies are needed to validate our findings.

Differential effect on survival of pelvic lymph node dissection at radical cystectomy for muscle invasive bladder cancer

PURPOSE To compare long-term cancer outcomes after radical cystectomy (RC) alone or RC with pelvic lymph node dissection (PLND) according to different age and comorbidities categories. METHODS Using the SEER-Medicare dataset, 3314 patients diagnosed with urothelial carcinoma of the urinary bladder and treated with RC alone or RC with PLND were identified. After propensity score matching to reduce potential selection bias, all cause mortality (ACM)-free and cancer specific mortality (CSM)-free survival rates were estimated. Multivariable regression models (MVA) addressed the effect of PLND on ACM and CSM. Subgroups analyses according to age and comorbidities were performed. RESULTS After matching, 688 and 688 patients treated with RC alone or RC with PLND remained. The 5-year ACM-free survival rate was 36 after RC alone and 45% after RC with PLND (p < 0001). In MVA, PLND exerted a protective effect on ACM (HR 0.77, p < 0.001). The 5-year CSM-free survival rate was 54 after RC alone and 65% after RC with PLND (p < 0.001). In MVA, PLND exerted a protective effect on CSM (HR 0.71, p < 0.001). Similar results were observed in younger (age ≤75) and healthier (CCI = 0) patients, where PLND exerted a protective effect on ACM (HR 0.64, p = 0.001) and CSM (HR 0.65, p = 0.01). Conversely, in older (age >75) and sicker (CCI ≥1) patients, PLND was not associated with ACM (HR 0.98, p = 0.8) or CSM (HR 1.01, p = 0.9). CONCLUSIONS RC with PLND is associated with improved all cause and cancer specific survival in younger and healthier RC candidates but not in older and sicker patients.

Gender-specific outcomes of bladder cancer patients: A stage-specific analysis in a contemporary, homogenous radical cystectomy cohort

INTRODUCTION Controversial findings regarding gender-specific oncological outcomes of urothelial carcinoma of the bladder (UCB) have recently been reported. The aim of this study was to analyze gender-specific outcomes using a stage-adjusted approach in a homogenous, contemporary radical cystectomy (RC) cohort. MATERIAL AND METHODS We prospectively collected data of 517 UCB patients treated with RC and pelvic lymphadenectomy without neoadjuvant chemotherapy at our institution between 1996 and 2010. Stage-adjusted uni- and multivariable Cox regression models analyzed the association of gender with disease recurrence, cancer-specific mortality and overall survival. RESULTS In total, 398 (77%) patients were male and 119 (23%) were female. Compared to men, women were more likely to have advanced tumor stages (p = 0.017), nodal metastasis (p = 0.047) and received more frequently adjuvant chemotherapy (p = 0.009). At a median follow-up of 44 months, there was no statistical difference in disease recurrence, cancer-specific mortality and overall survival between both genders when analyzed as a group. In stage-adjusted analyses, only women with non-invasive UCB were more likely to die of UCB compared to the male counterparts (p = 0.013). In gender-specific multivariable analyses that adjusted for standard clinico-pathologic features, pathologic tumor stage was an independent predictor for disease recurrence (p-values ≤0.047) and cancer-specific mortality (p-values ≤0.049), respectively. CONCLUSION Women present with more aggressive tumor biologic features at RC, however this did not translate into inferior outcomes compared to men in stage-specific analyses in our cohort. Tumor stage is the most important factor influencing the course of disease in both genders. Validation of our findings is warranted in a larger cohort.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment

BACKGROUND Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Prognostic value of the new Grade Groups in Prostate Cancer: a multi-institutional European validation study

Background:We aimed to assess the prognostic relevance of the new Grade Groups in Prostate Cancer (PCa) within a large cohort of European men treated with radical prostatectomy (RP).Methods:Data from 27 122 patients treated with RP at seven European centers were analyzed. We investigated the prognostic performance of the new Grade Groups (based on Gleason score 3+3, 3+4, 4+3, 8 and 9–10) on biopsy and RP specimen, adjusted for established clinical and pathological characteristics. Multivariable Cox proportional hazards regression models assessed the association of new Grade Groups with biochemical recurrence (BCR). Prognostic accuracies of the models were assessed using Harrell’s C-index.Results:Median follow-up was 29 months (interquartile range, 13–54). The 4-year estimated BCR-free survival (bRFS) for biopsy Grade Groups 1–5 were 91.3, 81.6, 69.8, 60.3 and 44.4%, respectively. The 4-year estimated bRFS for RP Grade Groups 1–5 were 96.1%, 86.7%, 67.0%, 63.1% and 41.0%, respectively. Compared with Grade Group 1, all other Grade Groups based both on biopsy and RP specimen were independently associated with a lower bRFS (all P<0.01). Adjusted pairwise comparisons revealed statistically differences between all Grade Groups, except for group 3 and 4 on RP specimen (P=0.10). The discriminations of the multivariable base prognostic models based on the current three-tier and the new five-tier systems were not clinically different (0.3 and 0.9% increase in discrimination for clinical and pathological model).Conclusions:We validated the independent prognostic value of the new Grade Groups on biopsy and RP specimen from European PCa men. However, it does not improve the accuracies of prognostic models by a clinically significant margin. Nevertheless, this new classification may help physicians and patients estimate disease aggressiveness with a user-friendly, clinically relevant and reproducible method.

Non-surgically related causes of erectile dysfunction after bilateral nerve-sparing radical prostatectomy

Background:Erectile dysfunction (ED) represents one of the most common long-term side effects in prostate cancer (PCa) patients treated with bilateral nerve-sparing radical prostatectomy (BNSRP). The aim of our study was to assess the influence of non-surgically related causes of ED in patients treated with BNSRP.Methods:Overall, 716 patients treated with BNSRP were retrospectively identified. All patients had complete data on erectile function (EF) assessed by the Index of Erectile Function-EF domain (IIEF-EF) and depressive status assessed by the Center for Epidemiologic Studies-Depression (CES-D) questionnaire. EF recovery was defined as an IIEF-EF of ⩾22. Kaplan–Meier analyses assessed the impact of preoperative IIEF-EF, depression and adjuvant radiotherapy (aRT) on the time to EF recovery. Multivariable Cox regression models were used to test the impact of aRT on EF recovery after accounting for depression and baseline IIEF-EF.Results:Median follow-up was 48 months. Patients with a preoperative IIEF-EF of ⩾22 had substantially higher EF recovery rates compared with those with a lower IIEF-EF (P<0.001). Patients with a CES-D of <16 had significantly higher EF recovery rates compared to those with depression (60.8 vs 49.2%; P=0.03). Patients receiving postoperative aRT had lower rates of EF compared with their counterparts left untreated after surgery (40.7 vs 59.8%; P<0.001). These results were confirmed in multivariable analyses, where preoperative IIEF-EF (P<0.001), depression (P=0.04) and aRT (P=0.03) were confirmed as significant predictors of EF recovery.Conclusions:Preoperative functional status and depression should be considered when counseling PCa patients regarding the long-term side effects of BNSRP. Moreover, the administration of aRT has a detrimental effect on the probability of recovering EF after BNSRP. This should be taken into account when balancing the potential benefits and side effects of multimodal therapies in PCa patients.