Luis A. Kluth

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder

Background:The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients.Methods:We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models.Results:With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients.Conclusion:The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.

Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder

PURPOSE Expression of T-cell co-regulatory proteins has been associated with worse outcomes in patients with UCB. We aimed to confirm these findings. MATERIALS AND METHODS The study comprised tissue microarrays from 302 consecutive UCB patients treated with RC and lymphadenectomy between 1988 and 2003, 117 matched lymph nodes, and 50 cases of adjacent normal urothelium controls, which were evaluated for B7-H1, B7-H3, and PD-1 protein expression by immunohistochemistry. RESULTS B7-H3 and PD-1 expression were increased in cancers compared to adjacent normal urothelium (58.6% vs 6% and 65% vs 0%, respectively; both p values < 0.001). Meanwhile, B7-H1 was expressed in 25% of cancers (n = 76). Expression of B7-H3, B7-H1, and PD-1 were highly correlated between the primary tumors and metastatic nodes, with concordance rates of 90%, 86%, and 78% for B7H3, B7H1 and PD-1, respectively. Expression was not associated with clinicopathologic features, disease recurrence, cancer-specific or overall mortality. However, for the subgroup of patients with organ-confined disease (n = 96), B7-H1 expression was associated with an increased risk of overall mortality (p = 0.02) on univariate and trended toward an association on multivariate analyses (p = 0.06). CONCLUSIONS B7-H1, B7-H3 and PD-1 are altered in a large proportion of UCB. B7-H1 and PD-1 expression are differentially upregulated in cancer versus normal urothelium. High correlation between expression in LN and expression in RC specimens was observed. While expression was not associated with clinicopathologic features or standard outcomes in all patients, B7-H1 expression predicted overall mortality after RC in the subset of patients with organ-confined UCB.

Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy

OBJECTIVE To investigate the impact of variant histologies of urothelial carcinoma of the bladder (UCB) on oncologic outcomes after radical cystectomy (RC). MATERIALS AND METHODS Data from 1984 UCB patients treated by RC without preoperative chemo- or radiotherapy were reviewed for histological differentiation and variants. We analysed the differences between pure UCB and UCB with variant histology, and those between the different histological variants using various stratifications. RESULTS Overall, 488 (24.6%) patients had UCB variants with squamous cell (11.4%) and glandular differentiation (3.8%) being the most common. Histological UCB variants were associated with advanced tumour stage, lymphovascular invasion and lymph node metastasis (all p-values<0.01) when compared to pure UCB. In univariable analyses, patients with non-squamous UCB variants were at significantly higher risk for disease recurrence and cancer-specific mortality than those with pure UCB patients (p-values=0.001) and those with squamous cell differentiated UCB (p-values=0.04); the latter two had the same risk. In multivariable analyses that adjusted for the effects of standard clinicopathologic characteristics, variant UCB histology was not associated with both survival end-points. In patients treated with adjuvant chemotherapy (n=492) there was no difference in cancer-specific survival between pure UCB, squamous cell differentiated UCB and other histological UCB variants. CONCLUSIONS A quarter of UCB patients treated with RC harboured histological UCB variants. Variant UCB histologies were associated with features of biologically aggressive disease. While variant UCB histology was associated with worse outcomes in univariable analyses, this effect did not remain significant in multivariable analyses.

Urine markers for detection and surveillance of bladder cancer.

OBJECTIVES Bladder cancer detection and surveillance includes cystoscopy and cytology. Urinary cytology is limited by its low sensitivity for low-grade tumors. Urine markers have been extensively studied to help improve the diagnosis of bladder cancer with the goal of complementing or even replacing cystoscopy. However, to date, no marker has reached widespread use owing to insufficient evidence for clinical benefit. MATERIAL AND METHODS Pubmed/Medline search was conducted to identify original articles, review articles, and editorials regarding urine-based biomarkers for screening, early detection, and surveillance of urothelial carcinoma of the bladder. Searches were limited to the English language, with a time frame of 2000 to 2013. Keywords included urothelial carcinoma, bladder cancer, transitional cell carcinoma, biomarker, marker, urine, diagnosis, recurrence, and progression. RESULTS Although several urinary markers have shown higher sensitivity compared with cytology, it remains insufficient to replace cystoscopy. Moreover, most markers suffer from lower specificity than cytology. In this review, we aimed to summarize the current knowledge on commercially available and promising investigational urine markers for the detection and surveillance of bladder cancer. CONCLUSIONS Well-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of biomarkers into clinical decision making will be of value for bladder cancer detection and screening in the future.

Gender-specific differences in clinicopathologic outcomes following radical cystectomy: An international multi-institutional study of more than 8000 patients

BACKGROUND The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood. OBJECTIVE To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI). RESULTS AND LIMITATIONS Female patients were older at the time of RC (p=0.033) and had higher rates of pathologic stage T3/T4 disease (p<0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p=0.022 and p=0.11, respectively). Female gender was an independent predictor for CSM (p=0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05). CONCLUSIONS We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.

Impact of peri‐operative blood transfusion on the outcomes of patients undergoing radical cystectomy for urothelial carcinoma of the bladder

To determine the association between peri‐operative blood transfusion (PBT) and oncological outcomes in a large multi‐institutional cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

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.

Robotic-assisted Radical Cystectomy With Extracorporeal Urinary Diversion for Urothelial Carcinoma of the Bladder: Analysis of Complications and Oncologic Outcomes in 175 Patients With a Median Follow-up of 3 Years

OBJECTIVE To report oncologic outcomes and complications after robotic-assisted radical cystectomy (RARC). MATERIALS AND METHODS From March 2004 to August 2011, 175 consecutive patients underwent RARC with extracorporeal urinary diversion at our institution by a single surgeon. The study design was prospective. Perioperative parameters and postoperative complications were prospectively collected using the modified Clavien system. Recurrence-free survival and cancer-specific survival curves were generated using the Kaplan-Meier method. RESULTS A total of 145 men and 30 women with a median age of 73 years and a median body mass index of 27 kg/m(2) underwent RARC. Four patients (2.3%) required conversion to open surgery because of difficulty to progress. One hundred nine patients (62%) underwent a transcutaneous ileal conduit, 40 patients (23%) an orthotopic neobladder, and 26 (15%) a continent cutaneous conduit. The median operating time was 360 minutes (interquartile range [IQR]: 300-420). The median estimated blood loss was 400 mL (IQR: 250-612), with a transfusion rate of 17.0%. The median postoperative length of stay was 7.0 days (IQR: 5.2-10). Early (<30 days) and late surgery-related complications (30-90 days) occurred in 74 (42%) and 59 (34%) patients, respectively. The perioperative mortality rate was 2.8%. The positive soft tissue surgical margins rate was 5%. The median number of lymph nodes removed was 19 (IQR: 12-28). The median follow-up was 37 months (IQR: 21.5-53.5). Actuarial recurrence-free survival and cancer-specific survival at 2, 3, and 5 years after RARC were 67%, 63%, 63% and 73%, 68%, 66%, respectively. CONCLUSION RARC achieved mid-term oncologic efficacy. Moreover, the complication rates were comparable with open radical cystectomy series.

Blood- and tissue-based biomarkers for prediction of outcomes in urothelial carcinoma of the bladder

OBJECTIVES Urothelial carcinoma of the bladder (UCB) is a highly heterogeneous malignancy that causes significant morbidity and mortality. Standard pathologic features (stage, grade, and nodal status) are insufficient to predict accurately a patients outcome. Biomarkers could help clinicians provide individualized prognostications and allow risk-stratified clinical decision making regarding surgical and medical treatment. This review summarizes the existing tissue- and blood-based biomarkers in UCB. MATERIAL AND METHODS A PubMed/Medline search was conducted to identify original articles regarding molecular biomarkers and UCB. Searches were limited to papers published in English. Keywords included urothelial carcinoma, bladder cancer, transitional cell, biomarker, marker, staining, cystectomy, recurrence or progression, survival, prediction, and prognosis. RESULTS The articles with the highest level of evidence were selected and reviewed, with the consensus of all the authors of this paper. CONCLUSIONS There is no doubt that a panel of biomarkers would eventually improve our clinical decision making regarding treatment and follow-up. However, to date, no biomarker panel is yet validated for daily clinical practice.

Outcomes of Ventral Onlay Buccal Mucosa Graft Urethroplasty in Patients after Radiotherapy

PURPOSE We evaluated stricture-free survival and functional outcomes of buccal mucosa graft urethroplasty in patients with urethral stricture disease after radiotherapy. MATERIALS AND METHODS We reviewed our urethroplasty database for patients with a radiotherapy history who underwent buccal mucosa graft urethroplasty between January 2009 and October 2013. We reviewed patient charts and the institutional, standardized, nonvalidated questionnaires administered to each patient postoperatively. Study end points included 1) the success rate, 2) continence status, 3) erectile function and 4) patient satisfaction postoperatively. Success was defined as stricture-free survival. RESULTS Of 38 men included in the study prostate cancer was the most common indication for radiotherapy in 35 (92.1%). External beam radiotherapy was performed in 24 cases (64.9%), brachytherapy was done in 8 (21.6%) and a combination of the 2 treatments was performed in 6 (13.5%). Strictures were in the bulbar/bulbomembranous urethra and had a median length of 3.0 cm (range 1.0 to 8.0). The overall success rate was 71.1% at a median followup of 26.5 months (range 1.0 to 50.0). Median time to stricture recurrence was 17.0 months (range 3.0 to 44.0). De novo urinary incontinence was observed in 4 patients (10.5%). Erectile function remained mostly unchanged compared to preoperative status. Study limitations include the small sample size and the lack of validated questionnaires. CONCLUSIONS At short-term to mid-term followup the success rate of ventral onlay buccal mucosa graft urethroplasty in patients with radiotherapy history seems acceptable. However, patients must be counseled about the increased risk of urinary incontinence. Longer followup is warranted to address long-term outcomes.