Impact of Preoperative Plasma Potassium Levels on Oncological Outcomes, Major Complications, and 30-Day Mortality in Bladder Cancer Patients Undergoing Radical Cystectomy.

INTRODUCTION AND OBJECTIVES: We examined the impact of preoperative plasma potassium levels (PPLs) on outcomes in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB), hypothesizing that potassium imbalances might influence outcomes. PATIENTS AND METHODS: In this retrospective study, 501 UCB patients undergoing RC from 2009 to 2017 at a tertiary center were analyzed. Blood samples collected a week prior to surgery defined normal and abnormal PPL based on institutional standards. We assessed overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), postoperative complications, 30-day mortality, and non-organ confined disease. Kaplan-Meier estimates, Cox proportional hazards, logistic regression, and decision curve analyses (DCA) were employed. RESULTS: 63 (13%) patients had abnormal preoperative PPLs, with 50 (10%) elevated and 13 (2.5%) decreased. In a 59 months median follow-up, 152 (31%) had disease recurrence, 197 (39%) died from any cause, and 119 (24%) from UCB. Multivariable cox regression analyses adjusting for perioperative parameters demonstrated abnormal PPL was associated with worse OS (HR=1.9, P=0.009), CSS (HR=2.8, P<0.001) and RFS (HR=2.1; P=0.007). Elevated preoperative PPLs also demonstrated significant associations with adverse outcomes in OS, CSS, and RFS (all P<0.05). In multivariable logistic regression analyses, abnormal and elevated PPLs were not associated with 30-day mortality, major 30-day postoperative complications, positive nodal disease, pT3/4 stage, and non-organ confined disease (all P>0.05). CONCLUSION: Abnormal and elevated preoperative PPLs correlate with adverse oncologic outcomes in UCB patients treated with RC. Pending external validation, preoperative PPLs might be a cost-effective, easily obtainable supplemental biomarker for enriching accuracy of outcome prediction in this highly variable maladie.

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

Predictive Impact of Prognostic Nutritional Index on Pembrolizumab for Metastatic Urothelial Carcinoma Resistant to Platinum-based Chemotherapy.

BACKGROUND/AIM: We investigated the prognostic nutritional index (PNI), comprised of lymphocytes and albumin, as a potential prognosticator of metastatic urothelial carcinoma (mUC) patients receiving pembrolizumab. PATIENTS AND METHODS: Sixty-five patients were retrospectively enrolled and classified as low (<40) and high (≥40) based on pretreatment PNI. Progression-free survival (PFS), overall survival (OS) and response rates were evaluated. RESULTS: In the low PNI group, significantly shorter PFS and OS were observed. PNI was shown to be an independent predictor of PFS and OS in the multivariate analysis. C-index for both PFS and OS improved with the addition of PNI to the model described in the KEYNOTE-045 study. Significantly more patients experienced initial disease progression in the low PNI group. CONCLUSION: PNI is a useful predictor of prognosis and disease progression in mUC patients receiving pembrolizumab.

Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.

OBJECTIVE: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. RESULTS: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. CONCLUSION: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.

Systematic Literature Review and Meta-Analysis of Response to First-Line Therapies for Advanced/Metastatic Urothelial Cancer Patients Who Are Cisplatin Ineligible.

OBJECTIVE: The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible. MATERIALS AND METHODS: SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network's recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98). CONCLUSIONS: The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.

Pelvic lymph node dissection during radical cystectomy for muscle-invasive bladder cancer.

Radical cystectomy is the gold-standard treatment option for muscle-invasive and metastatic bladder cancer. At the time of cystectomy, up to 25% of patients harbour metastatic lymph node deposits. These deposits most frequently occur in the obturator fossa, but can be as proximal as the interaortocaval region. Thus, the use of concurrent pelvic lymph node dissection (PLND) with cystectomy has been increasingly reported. Data from studies including many patients suggest substantial oncological benefit in PLND cohorts versus non-PLND cohorts, irrespective of pathological nodal status. Additionally, PLND provides useful prognostic information, including disease burden, lymph node density, and extracapsular extension of metastatic lymph nodes. Accordingly, the National Comprehensive Cancer Network guidelines advocate the use of PLND during radical cystectomy for muscle-invasive bladder cancer. Despite this recommendation, a lack of consensus exists regarding the optimal PLND template. Comparative series suggest that extended PLND provides improved recurrence-free survival and cancer-specific survival compared with more limited PLND templates. More extensive templates (such as super-extended PLND) provide no additional survival benefit at the potential cost of increased operative time and patient morbidity. In addition to extended PLND templates, increased nodal harvest confers an oncological benefit in patients with node-positive disease or in patients with node-negative disease. Accordingly, recommendations for a minimum nodal yield have been proposed. Despite the growing body of evidence, formal recommendations by oncological and urological authoritative bodies have been limited owing to the lack of randomized data and level I evidence.

Impact of Primary Tumor Location on Survival from the European Organization for the Research and Treatment of Cancer Advanced Urothelial Cancer Studies.

PURPOSE: The prognostic relevance of primary location of urothelial carcinoma on survival has been poorly investigated. MATERIALS AND METHODS: We used prospectively collected data from 3 European Organization for the Research and Treatment of Cancer advanced urothelial carcinoma studies, including 30924 (methotrexate, vinblastine, doxorubicin and cisplatin vs high dose methotrexate, vinblastine, doxorubicin and cisplatin), 30986 (methotrexate, carboplatin and vinblastine vs gemcitabine and cisplatin in patients who were not candidates for cisplatin) and 30987 (gemcitabine and cisplatin-paclitaxel vs gemcitabine and cisplatin in candidates for cisplatin). Patients were grouped by primary tumor location as those with bladder cancer or upper tract urothelial carcinoma. Progression-free and overall survival was tested by tumor location using Cox proportional hazard regression stratified by study and treatment using 2-sided α = 0.05. RESULTS: Of the 1,039 patients 878 (85.3%) and 161 (14.7%) had bladder cancer and upper tract urothelial carcinoma, respectively. Patients with bladder cancer had better performance status and were more likely to be male (p = 0.008 and <0.074, respectively). By a median followup of 4.8 years (IQR 4.0-6.7) 733 patients had died and 925 had experienced disease progression. Overall and progression-free survival did not differ significantly between bladder and upper tract urothelial carcinoma cases (p = 0.3 and 0.7, respectively), even after adjusting for the effects of Bajorin risk group by each tumor location. When upper tract urothelial carcinoma was considered separately, patients with primary ureteral tumors had better overall survival than patients with primary bladder cancer (OR = 0.74, p = 0.047). However, this association did not remain significant after adjusting for Bajorin risk group (p = 0.05). CONCLUSIONS: Primary tumor location had no impact on progression-free or overall survival in patients with locally advanced or metastatic urothelial carcinoma treated with platinum based combination chemotherapy.

Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study.

PURPOSE: We report for the first time the activity and safety of Unithermia(®) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia(®) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia(®) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

Safety and efficacy of combination therapy with low-dose gemcitabine, paclitaxel, and sorafenib in patients with cisplatin-resistant urothelial cancer.

Various regimens including molecular targeted agents have been examined in patients with cisplatin (CDDP)-resistant urothelial cancer (UC). However, some studies have been stopped owing to the development of severe adverse events. The main aim of this study was to examine the anticancer effects, changes in the quality of life (QoL), and safety of combined therapy of low-dose gemcitabine, paclitaxel, and sorafenib (LD-GPS) in patients with CDDP-resistant UC. Twenty patients were treated with gemcitabine (700 mg/m(2) on day 1), paclitaxel (70 mg/m(2) on day 1), and sorafenib (400 mg/day on days 8-22). QoL and pain relief were evaluated using the short-form survey (SF)-36 for bodily pain and the visual analog scale (VAS). VAS scores were significantly decreased by both the second- and third-line therapies (P = 0.012 and 0.028, respectively). The bodily pain score from the SF-36 survey was also significantly (P = 0.012) decreased. Complete responses, partial responses, and stable disease were found in 0 (0.0 %), 1 (5.0 %), and 13 patients (65 %), respectively. The median (interquartile range) period of overall survival after starting of this therapy was 7 (5-11) months. Three patients (15.0 %) stopped therapy because of grade 3 fatigue and hand-foot reactions. LD-GPS therapy was well tolerated by patients with CDDP-resistant UC. QoL was maintained, and improvements in their pain levels were found after treatment; pain relief was detected after third-line therapy. We suggest that this treatment regimen is worthy of consideration as second- and third-line therapy for patients with CDDP-resistant UC.

Impact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: results of the international collaboration on primary urethral carcinoma.

BACKGROUND: To investigate the impact of perioperative chemo(radio)therapy in advanced primary urethral carcinoma (PUC). PATIENTS AND METHODS: A series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in 10 referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on overall survival (OS). The median follow-up was 21 months (mean: 32 months; interquartile range: 5-48). RESULTS: Neoadjuvant chemotherapy (NAC), neoadjuvant chemoradiotherapy (N-CRT) plus adjuvant chemotherapy (ACH), and ACH was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of NAC/N-CRT was associated with clinically node-positive disease (cN+; P = 0.033) and lower utilization of cystectomy at surgery (P = 0.015). The objective response rate to NAC and N-CRT was 25% and 33%, respectively. The 3-year OS for patients with objective response to neoadjuvant treatment (complete/partial response) was 100% and 58.3% for those with stable or progressive disease (P = 0.30). Of the 26 patients staged ≥cT3 and/or cN+ disease, 16 (62%) received perioperative chemo(radio)therapy and 10 upfront surgery without perioperative chemotherapy (38%). The 3-year OS for this locally advanced subset of patients (≥cT3 and/or cN+) who received NAC (N = 5), N-CRT (N = 3), surgery-only (N = 10) and surgery plus ACH (N = 8) was 100%, 100%, 50% and 20%, respectively (P = 0.016). Among these 26 patients, receipt of neoadjuvant treatment was significantly associated with improved 3-year relapse-free survival (RFS) (P = 0.022) and OS (P = 0.022). Proximal tumor location correlated with inferior 3-year RFS and OS (P = 0.056/0.005). CONCLUSION: In this series, patients who received NAC/N-CRT for cT3 and/or cN+ PUC appeared to demonstrate improved survival compared with those who underwent upfront surgery with or without ACH.

Clinical response to induction chemotherapy predicts improved survival outcome in urothelial carcinoma with clinical lymph nodal metastasis treated by consolidative surgery.

BACKGROUND: To determine the indications for post-chemotherapy consolidative surgery in patients with clinical lymph node (LN) metastatic (cN+) urothelial carcinoma (UC). METHODS: Sixty UC patients with measurable cN+ but without detectable systemic visceral/bone dissemination received induction platinum-based chemotherapy. Consolidative surgery was offered to all patients except for those with progressive disease. We retrospectively analyzed the clinicopathological response to induction chemotherapy and identified prognostic factors for overall survival (OS). RESULTS: The primary cancer site was the urinary bladder in 31 patients (52 %) and upper urinary tract in 29 (48 %). The median number of chemotherapy courses was 4. Forty-five patients (75 %) showed a clinically objective response to the induction chemotherapy. Fifty-one patients (85 %) underwent subsequent consolidative surgery. Histopathological analysis indicated pT0 status in 10 (20 %) and pN0 in 17 (33 %). When all 60 patients were considered, clinical tumor response was found to be significantly correlated with achievement of pathological complete response. At the median follow-up of 22 months, the median progression-free survival and OS periods were excellent: 18.6 and 31.6 months, respectively. In the multivariate analysis, clinical tumor response was found to be an independent pre-surgical prognostic factor for OS, and pathologically negative lymph node, negative resection margin, more LNs removed, and negative lymphovascular invasion were found to be independent post-surgical prognostic parameters for OS. CONCLUSIONS: The median OS in induction chemotherapy followed by consolidative surgery was very encouraging. Our results suggest that achieving a good clinical response to pre-surgical induction chemotherapy is a good indication for subsequent consolidative surgery in UC patients with cN+ to improve OS through a good pathological response.

Reporting trends and prognostic significance of lymphovascular invasion in muscle-invasive urothelial carcinoma: a population-based study.

OBJECTIVES: To investigate reporting patterns and outcomes associated with lymphovascular invasion in a general population setting. METHODS: We identified all cystectomy patients with muscle-invasive urothelial cancer in Ontario, Canada, 1994-2008. Surgical pathology reports were analyzed for pathological variables including lymphovascular invasion. Lymphovascular invasion reporting patterns were described over time. A Cox proportional hazards model was used to evaluate the association of lymphovascular invasion with survival. RESULTS: Of the 2802 cases identified, lymphovascular invasion status was reported in 75%. Lymphovascular invasion reporting significantly improved over the study period and was correlated with poor prognostic pathological features (T stage and N stage). Comprehensive cancer center status was not consistently associated with lymphovascular invasion reporting. Patients with lymphovascular invasion had substantially lower survival than patients who were lymphovascular invasion-negative or whose lymphovascular invasion status was unstated (P < 0.001). Lymphovascular invasion was independently associated with survival in patients regardless of lymph node metastasis. After adjusting for age, stage, comorbidity, margin status and adjuvant chemotherapy, lymphovascular invasion remained strongly associated with reduced survival (hazard ratio 1.98, 95% confidence interval 1.71-2.29). CONCLUSIONS: Although routine reporting of lymphovascular invasion has improved over the years, pathologists appear to be biased towards evaluating lymphovascular invasion in patients with high-stage disease. Despite this bias, lymphovascular invasion remains an important prognostic factor among patients treated by cystectomy. Pathologists in general practice should report lymphovascular invasion status more consistently and urologists should hold their pathology colleagues to a higher standard.

The predictive value of GSTT1 polymorphisms in predicting the early response to induction BCG therapy in patients with non-muscle invasive bladder cancer.

INTRODUCTION: We evaluated the predictive value of glutathione S transferase mu (GSTM1) and theta (GSTT1) polymorphisms in early response to bacillus Calmette-Guérin (BCG) induction therapy in patients with primary non-muscle invasive bladder cancer. METHODS: GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction using blood genomic DNA from 135 patients with primary non-muscle invasive bladder cancer who were being treated with a single induction course of BCG. BCG nonresponsiveness (early BCG failure) was defined as a tumor recurrence or progression within 12 months after BCG induction therapy. The predictive value of GST polymorphisms was evaluated by Kaplan-Meier analysis and multivariate logistic regression models. RESULTS: Patients carrying a GSTT1-positive genotype demonstrated a higher likelihood of early BCG failure regardless of cigarette smoking. After stratification based on the tumor stage and grade, the high-risk group (T1G3) with a GSTT1-positive genotype showed a 14-fold higher risk of early BCG failure compared with those with a GSTT1-null genotype. In a combined analysis of 2 genes, the GSTT1-positive/GSTM1-null genotype had a higher risk of BCG nonresponsiveness compared with the GSTT1-null/GSTM1-null genotype (odds ratio = 4.17, 95% CI: 1.54-11.26). By multivariate logistic regression analysis, the GSTT1-positive genotype was an independent predictor of early BCG failure (odds ratio = 3.67, 95% CI: 1.61-8.38). Kaplan-Meier estimates revealed a significant difference in disease-free survival depending on the GSTT1 genotype (log rank test, P = 0.038). CONCLUSIONS: The results of this study suggest that the GSTT1-positive genotype is an independent predictor of early BCG failure. These results can help determine whether patients would benefit from adjuvant BCG treatment or may require more aggressive alternative therapies.

Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.

BACKGROUND: We assessed effectiveness, safety, and tolerability of paclitaxel or fluorouracil when added to radiation plus cisplatin followed by adjuvant chemotherapy in a programme of selected bladder preservation for patients with muscle invasive bladder cancer. METHODS: In our randomised phase 2 trial, we enrolled patients with T2-4a transitional cell carcinoma of the bladder at 24 medical centres in the USA. We randomly allocated patients to receive paclitaxel plus cisplatin (paclitaxel group) or fluorouracil plus cisplatin (fluorouracil group) with twice-daily radiation in random block sizes per site on the basis of clinical T-stage (T2 vs T3-4). Patients and physicians were aware of treatment assignment. All patients had transurethral resection of bladder tumour and twice-daily radiotherapy to 40·3 Gy, along with allocated chemotherapy, followed by cystoscopic and biopsy assessment of response. Patients who had a tumour response with downstaging to T0, Tcis, or Ta received consolidation chemoradiotherapy to 64·3 Gy, with the same chemotherapy regimen as in the induction phase. Patients received adjuvant cisplatin-gemcitabine-paclitaxel after the end of chemoradiotherapy. If, after induction, persistent disease was graded as T1 or worse, we recommended patients undergo cystectomy and adjuvant chemotherapy. We assessed the primary endpoints of rates of treatment completion and toxic effects in all randomly allocated patients. This study is registered with ClinicalTrials.gov, number NCT00055601. FINDINGS: Between Dec 13, 2002, and Jan 11, 2008, we enrolled 97 patients, of whom 93 were eligible for analysis. Median follow-up was 5·0 years (IQR 5·0-6·2). Of 46 patients in the paclitaxel group, 45 (98%) completed induction (16 [35%] with grade 3-4 toxicity), 39 (85%) completed induction and consolidation (11 [24%] with grade 3-4 toxicity due to consolidation), and 31 (67%) completed the entire protocol with adjuvant chemotherapy. 34 (85%) of 40 assessable patients in the paclitaxel group had grade 3-4 toxicity during adjuvant chemotherapy. Of 47 patients in the fluorouracil group, 45 (96%) completed induction (nine [19%] with grade 3-4 toxicity), 39 (83%) completed induction and consolidation (12 [26%] had grade 3-4 toxicity due to consolidation), and 25 (53%) completed the entire protocol with adjuvant chemotherapy. 31 (76%) of 41 assessable patients in the fluorouracil group had grade 3-4 toxicity during adjuvant chemotherapy. Five (11%) patients treated with the paclitaxel regimen and three (6%) patients treated with the fluorouracil regimen developed late grade 3-4 radiotherapy toxicities. 11 (24%) patients treated with the paclitaxel regimen and 16 (34%) patients treated with the fluorouracil regimen developed late grade 3-4 toxicities unrelated to radiotherapy. One patient (in the fluorouracil group) died during follow-up. Six (13%) patients in the paclitaxel group and in three (6%) patients in the fluorouracil group discontinued due to treatment-related toxicity. INTERPRETATION: In the absence of phase 3 data, our findings could inform selection of a bladder-sparing trimodality chemotherapy regimen for patients with muscle invasive bladder cancer. FUNDING: US National Cancer Institute.

Lymph node density for patient counselling about prognosis and for designing clinical trials of adjuvant therapies after radical cystectomy.

UNLABELLED: What's known on the subject? and What does the study add? Patients with positive lymph nodes at radical cystectomy have a poor prognosis. The actual outcome of patients varies based on many factors, among which lymph node density has emerged as being more informative than nodal status of TNM staging. We combined clinical data from two major cancer centres in the USA and identified patients with an adequate lymphadenectomy and no perioperative chemotherapy to understand the natural history of the disease. Using this information, we created prognostic tools incorporating lymph node density that can be used for risk stratification, patient counselling and clinical trial design. OBJECTIVE: • To develop a clinical tool based on lymph node density (LND) for patient counselling after radical cystectomy and for design of clinical trials of adjuvant therapies after radical cystectomy. PATIENTS AND METHODS: • Using pooled data from two comprehensive cancer centres, we identified patients with lymph node metastases after radical cystectomy who received an adequate lymph node dissection according to existing literature (resection of eight or more nodes). • Only patients who had not received neoadjuvant or adjuvant chemotherapy were included to ensure that prediction models were based on the natural course of the disease. • Thresholds for LND ranging from 5% to 35%, in 5% increments, were used to dichotomize the study population. Within each set of two groups, the Kaplan-Meier product-limit estimator was used to estimate disease-specific survival (DSS) for each group, and Cox proportional hazards regression was used to test the significance of differences in DSS between the group with higher LND and the group with lower LND. • Tables and graphs showing the relationship between LND categories and 2-year and 5-year estimated DSS were created to aid in clinical decision-making. RESULTS: • LND was valuable as a tool for stratifying node-positive patients into different risk groups based on expected survival. • At each LND threshold from 10% to 35%, patients with higher LND had significantly worse DSS than patients with lower LND (P ≤ 0.001). • As expected, DSS in the higher-LND group worsened with each 5% increase in LND threshold: patients with LND > 35% had a 5-year DSS rate of 4%. • Using our data as a tool, multiple cut-offs can be employed to categorize patients into various risk groups with different risk. For example, patients with LND ≤ 10% have an estimated 5-year DSS rate of 61.9%, whereas patients with LND > 15% have an estimated 5-year DSS rate of 19.2%. CONCLUSIONS: • Patients with node-positive bladder cancer have poor outcomes, and survival varies widely according to LND. • Categorical LND should be used to risk-stratify patients for counselling regarding prognosis. • Furthermore, categorical LND should be used as a tool for designing and reporting on clinical trials of adjuvant therapies.

Towards bloodless cystectomy: a 10-year experience of intra-operative cell salvage during radical cystectomy.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Guidance from the UK National Institute for Health and Clinical Excellence (NICE) on the use of intraoperative cell savage (ICS) has been in place for over 3 years and recommends its routine usage in all patients undergoing radical pelvic urological surgery. The current series describes the contribution of ICS to contemporary blood conservation strategies and the goal of 'bloodless' cystectomy. OBJECTIVE: • To describe a 10-year experience of intra-operative cell salvage (ICS) during radical cystectomy at a regional cancer centre. PATIENTS AND METHODS: • Between 1(st) January 2001 and 31(st) December 2010, 213 consecutive patients underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer, with an ICS suction device used in theatre. • Surgery was performed by one of three consultant surgeons using an open technique with lymph node clearance to the iliac bifurcation. Orthotopic bladder substitution was performed in 25% of patients overall. • ICS data were collected prospectively on an electronic database and the institutional database was then cross-referenced with a complete review of patients' medical records, laboratory results and radiological investigations retrospectively. • Data collected included patient demographics, haemoglobin levels before and after surgery, the volume of ICS blood collected and re-infused, complications related to ICS usage, the volume of allogeneic red blood cells (RBCs) transfused, length of stay and overall patient survival at 3 and 5 years after surgery. RESULTS: • In all 213 cases described, ICS was used without complication, with no recorded episodes of device failure and no complications related to the use of cell salvage. • Overall, 91% of patients received ICS blood and 28% of patients avoided any further transfusion products. • The median (range) follow-up for the cohort was 24 (9-119) months. • Seventy percent of the transfusion requirement for patients who underwent surgery in 2001 was met using allogeneic RBC transfusion but by 2010, as blood loss markedly reduced, ICS blood was able to provide ∼70% of overall transfusion requirements. As a consequence, the percentage of patients avoiding an allogeneic RBC transfusion significantly increased during the 10-year period, such that 70% of patients avoided allogeneic RBC transfusion in 2010 compared with only 10-20% in the period 2001-2003 • The overall survival rate at 3 and 5 years was 58% and 49%, respectively. CONCLUSIONS: • In conclusion, the use of ICS during radical cystectomy is safe; it is capable of meeting the majority of or, in some cases, the total blood product requirement for individual patients. As a result, it decreases the need for allogeneic RBC transfusion and hence the associated risks. Current follow-up shows no apparent risk of decreased long-term survival from an oncological perspective. • The authors advocate routine availability of ICS for all major urological oncology cases.

The risk profiles of three clinical types of carcinoma in situ of the bladder.

OBJECTIVE: • To further clarify the risk profiles of three clinical types of carcinoma in situ (CIS) of the bladder. MATERIALS AND METHODS: • Population-based data from the Comprehensive Cancer Centre Middle Netherlands, as part of the nationwide Netherlands Cancer Registry, were used for patients presenting with CIS in the period from 1987 to 2009. • Patients with muscle-invasive bladder cancer on primary diagnosis were excluded. The patients were divided into three groups according to their 'clinical type', being primary, concomitant or secondary CIS. RESULTS: • Overall, 90 patients with CIS were identified with a mean age of 63.4 years, predominantly men (91.1%). Primary CIS (P-CIS) was found in 43 patients (47.8%), concomitant CIS (C-CIS) in 21 patients (23.3%) and secondary CIS (S-CIS) in 26 patients (28.9%). Mean follow up was 81.3 months (range 8-222 months). Recurrence of disease was observed in 68.9% of patients, with significantly more recurrences in the S-CIS group (88.5%). • Progression to muscle-invasive disease was seen in 17 patients (18.9%): eight patients (18.7%) with P-CIS, four (19.0%) with C-CIS and five (19.2%) with S-CIS. Overall, 29 patients underwent a cystectomy, equally distributed over the three groups. The duration of bladder preservation was worse in the C-CIS group but did not differ significantly between the groups. • Overall survival at 5 years was 79.6% for the total group, with poorer results for the C-CIS group, although the difference was not significant. CONCLUSIONS: • Carcinoma in situ is clearly an entity that requires meticulous treatment and thorough follow up because of its high recurrence rate (68.9%) and high rate of progression to muscle-invasive bladder cancer (18.9%). • The C-CIS group appears to have a poorer prognosis with a shorter duration of bladder preservation and a worse overall survival.

[EMMPRIN (CD147). A prognostic and potentially therapeutic marker in urothelial cancer]. / EMMPRIN (CD147). Ein prognostischer und potenzieller therapeutischer Marker im Urothelkarzinom.

In 50% of all cases, bladder cancer patients develop tumor progression despite modern surgical methods such as radical cystectomy. A solution to the problem might be the identification and understanding of molecular biomarkers which could result in the development of advanced methods with better preventive, diagnostic, and therapeutic potential. One suitable approach is the identification of a bladder cancer-specific molecular marker in order to enhance patients' outcome. We and others have identified EMMPRIN as a prognostic biomarker in a variety of tumor diseases. EMMPRIN (CD147, extracellular matrix metalloproteinase inducer) is a cell surface protein that is expressed among other cell types, in particular in tumor cells. Since its first description in 1982 it is established that overexpression of EMMPRIN correlates with tumor progression and patient outcome. EMMPRIN expression levels can be used as an independent prognostic factor for survival. Recently, EMMPRIN has been defined as a potential target for tumor therapy in preclinical studies.

[Targeted therapy for metastatic bladder cancer]. / Targeted-Therapie des metastasierten Urothelkarzinoms.

The current therapy concept for metastatic bladder cancer is chemotherapy with gemcitabine and cisplatin as the first line protocol. Within the last 20 years no real progress could be achieved; the median survival is 14 months, though many different protocols have been tested. Expression analyses of growth factor receptors in human tumor tissue showed that expression of certain receptors is correlated with a severe clinical course.For many of these growth factor receptors pharmacological inhibitors are available in order to perform targeted therapy. The following review gives a survey of current studies on targeted therapy of metastatic bladder carcinoma.

Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer.

OBJECTIVES: To determine the expression patterns and prognostic value of S100A2 and S100A4 in surgical specimens from radical cystectomy for transitional cell carcinoma of the urinary bladder. METHODS: Immunohistochemical staining for S100A2 and S100A4 was performed in 92 archived radical cystectomy and 38 normal specimens. The immunoreactivity of these proteins was stratified on a 0 to 6 scale and then correlated with the pathologic features and clinical outcome. RESULTS: S100A2 expression was significantly decreased in the bladder cancer specimens compared with the controls (P <0.0001), and S100A4 expression was significantly greater in the bladder cancer specimens (P = 0.03). The loss of expression of S100A2 and increased expression of S100A4 were associated with muscle invasion (P <0.05). These alterations in expression were also associated with a greater risk of disease progression and a decreased chance of cancer-specific survival at a median follow-up of 25.3 months (P <0.0001 for both). After adjusting for the effects of the pathologic findings, S100A4 expression remained a significant predictor of disease progression (P <0.0001) and cancer-specific survival (P <0.0001). CONCLUSIONS: S100A4 appeared to be an independent predictor for the treatment outcome in bladder cancer. The expression patterns of S100A2 and S100A4 correlated well with the pathologic stage, disease progression, and cancer-specific mortality. This finding could aid in identifying more biologically aggressive cancers and thus patients who might benefit from more intensive adjuvant therapy.