Bladder Cancer
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Bladder cancer is a disease in which malignant cells arise in the bladder. Symptoms can include blood in the urine, pain during urination, increased frequency of passing urine, or feeling the need to urinate but with nothing coming out. The bulk of bladder cancers are histlogically classed as transitional cell carcinomas which arise in the uroepithelium (lining of the bladder). Other types include squamous cell carcinomas, and adenocarcinomas. Treatment will depend on how far the tumour has invaded the surrounding tissues, and if it has spread to other parts of the body. World-wide about 260,000 people are diagnosed with bladder cancer each year.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Molecular Biology of Bladder Cancer
Urinary System Cancers

Information Patients and the Public (16 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Hammam O, Wishahiz M, Khalil H, et al.
Expression of cytokeratin 7, 20, 14 in urothelial carcinoma and squamous cell carcinoma of the Egyprian urinary bladder cancer.
J Egypt Soc Parasitol. 2014; 44(3):733-40 [PubMed] Related Publications
This study estimated the expression of CK-7, CK14, and CK-20 protein in human bladder carcinoma, urothelial carcinoma (UC) in comparison to squamous cell carcinoma (SCC) and to show its possible correlation to clinicopathologic parameters (grade and stage and bilharziasis), and investigate whether cytokeratin 14 immunostaining may be useful to detect early squamous metaplasia in bladder biopsies and in association with UC. We evaluated the bladder tissues of 200 patients with bladder carcinoma, 150 patients had UC, and 50 patients had SCC. Imunohistochemical technique was used for detection of CK7, CK14 and CK20 monoclonal antibodies. The mean age of the patients was 55 years (range 51-70 years). The UC were classified according to grades into grade I, II and III in 20, 40 and 90 cases, respectively. Stages of UC were: Ta in 10, T1 in 60 and 90 patients with muscle-invasive T2-3. In UC cases 105 /150 (70%) were positive for over expression of CK20. In the same group of UC 120/150 (80) were positive for over expression of CK7. Negative expression was found in SCC cases. A High grades of the UC were associated with decrease expression of CK 20, there were 20 (100%) in GI, 35 (87.5%) in GII, 50 (68.6%) in GIII (P <0.01), and an increase expression of CK7 4 (20%) in GI, 26 (65%) in GII, 90(100%) in GIII (P <0.01). CK20 expression decreased as the tumor stages increased, it was 15 (100%) in Ta, 50 (83.3%) in T1, 40 (50%) in T2-3 (P <0.01), while CK7 showed increase expression in 2 cases with Ta tumor (20%), 38 (47.5%) in T1, 80 (100%) in T2-T3 (P <0.01). The present study confirmed that CK14 is expressed in SCC and in UC with squamous differentiation.

Hammam O, Wishahi M, Hindawi A, et al.
Superiority of fluorescent in situ hybridization over immunohistochemistry in detection of HER2 gene in carcinoma of the urinary bladder associated with and without schistosomiasis.
J Egypt Soc Parasitol. 2014; 44(3):719-31 [PubMed] Related Publications
HER2 is an oncogene encoding a type 1 tyrosine kinase growth factor receptor and the role of HER2 in the development of numerous types of human cancer is still understood and correlates with clinical outcome, poor prognosis, it is a predictor factor for poor response to chemotherapy. HER2 overexpression is associated with reduced disease free and overall survival. Patients who have HER2 negative expression have a poor prognosis. The aim of the present study is to explore the accuracy of detection of expression of HER2 protein by two different techniques of immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH). The two techniques were applied to sixty two patients that included different cell types of carcinoma of the bladder, benign bilharzial lesions and control. Characteristics of the 62 patients are: 10 chronic cystitis, 19 squamous cell carcinoma (SCC) with schistosomiasis, 33 urothelial carcinoma (UC) schistosomal and non-schistosomal, ten healthy individuals without schistosomiasis served as controls. Gene amplification of HER2 was done using FISH and protein expression of HER2 by IHC. The study was applied on archival data of formalin-fixed paraffin embedded tissues and patient clinical data and follow up for 5 years. Overexpression of HER2 protein was found in 30/52 (57.7%). Fourteen cases had score of 2+, and sixteen cases had score of 3+. Using FISH technique it showed more accurate detection of HER2 gene as those fourteen cases who had score of 2+ had been found to be 5 out of 14 were positive for gene over expression, the other sixteen who had score of 3+ all were positive for gene amplification. HER2 protein and gene was found to be significantly overexpressed in carcinoma of the bladder in both cell types SCC and UC with or without schistosomiasis compared to the benign lesions and control groups (P <0.01) by both techniques. There is significant increase in expression of HER2 protein and gene in SCC compared to UC (P< 0.01). In UC overexpression of HER2 protein and gene was evident in all stages Ta, T1, T2-4. HER2 protein and gene overexpressed in different grades of UC. In SCC HER2 protein and gene had overexpression in different stages and grades.

Related: FISH

Mazzucchelli R, Scarpelli M, Galosi AB, et al.
Pathology of upper tract urothelial carcinoma with emphasis on staging.
Int J Immunopathol Pharmacol. 2014 Oct-Dec; 27(4):509-16 [PubMed] Related Publications
Classification of upper tract urothelial preneoplastic and neoplastic lesions mirrors that of the urinary bladder, with all lesions of the bladder urothelium being possible in the upper tract and vice versa. There are three major groups of non-invasive urothelial neoplasms: flat, papillary, and inverted. These three groups share a similar morphological spectrum of intraurothelial changes, ranging from hyperplasia to dysplasia to carcinoma in situ. However, they differ in terms of architectural growth pattern compared to the surrounding non-neoplastic mucosal surface. Infiltrating urothelial carcinoma is defined as a urothelial tumor that invades beyond the basement membrane. Unlike in non-invasive papillary urothelial neoplasms (pTa), the role of histologic grade in pT1 and higher stage tumors has been suggested to be of only relative importance. The vast majority of tumors of the upper urinary tract are urothelial carcinoma. More commonly seen, however, are foci of squamous differentiation and, less frequently, glandular differentiation. Pure urothelial carcinomas also display a wide range of variant morphologies, and recognition of these morphologies is important for diagnosis, classification, and prognosis.

Kobayashi T, Owczarek TB, McKiernan JM, Abate-Shen C
Modelling bladder cancer in mice: opportunities and challenges.
Nat Rev Cancer. 2015; 15(1):42-54 [PubMed] Related Publications
The prognosis and treatment of bladder cancer have improved little in the past 20 years. Bladder cancer remains a debilitating and often fatal disease, and is among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as to affect its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described, and in particular, few that develop invasive cancer phenotypes. This Review focuses on opportunities for improving the landscape of mouse models of bladder cancer.

Knowles MA, Hurst CD
Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity.
Nat Rev Cancer. 2015; 15(1):25-41 [PubMed] Related Publications
Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. Low-grade non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle-invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.

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Garg M
Prognostic and therapeutic applications of the molecular events in clinical management of urothelial carcinoma of bladder.
J Exp Ther Oncol. 2014; 10(4):301-16 [PubMed] Related Publications
Urothelial carcinoma of bladder being the commonest malignancy of the urinary tract progresses through successive accumulation of genetic alterations and bears high metastatic potential. Despite significant advances in its prognosis and treatment, including surgical techniques, various adjuvant therapies, radical cystectomy and robot-assisted radical cystectomy, tumor recurs with a poor 5 year survival rate thereby necessitating the need to institute an additional form of novel target based therapies to improve the overall outcome. Improved understanding of the molecular pathways critical for both early and late stage disease not only leads to better prognostication but may also enhance therapeutic index. This review article highlights the recent progress in the development of novel anti-cancer targeted therapies that may modulate clinical response of cytotoxic drugs with minimal adverse side effects and provide insight for the potential reversion of the resistance in patients failing therapy.

Mazul-Sunko B, Gilja I, Jelisavac M, et al.
Thoracic epidural analgesia for radical cystectomy improves bowel function even in traditional perioperative care: a retrospective study in eighty-five patients.
Acta Clin Croat. 2014; 53(3):319-25 [PubMed] Related Publications
Radical cystectomy is associated with significant morbidity and mortality due to complex surgery and comorbidities associated with advanced age of patients. In contrast to the surgery, which is clearly the procedure of choice for patients with invasive bladder cancer, the opti- mal anesthesiologic method is still under debate. Therefore, we retrospectively analyzed 85 patients having undergone radical cystectomy at our institution, either under combined epidural-general anesthesia (CEGA) or opioid based general anesthesia (GA). The intraoperative blood loss was significantly lower in CEGA group (497.37 ± 354.13) than in GA group (742.31 ± 403.69; p = 0.006), due to induced hypotension. Consequently, blood transfusion requirements were lower in CEGA group (107.20 ± 263.92) than in GA group (388.18 ± 321.32; p = 0.001). The incidence of postoperative ileus was also lower in CEGA group (p = 0.024). There was no difference in analgesic efficacy, but a trend towards lower incidence of venous thrombosis and infection was noticed. The results of our study suggest that epidural anesthesia might have specific advantages in patients undergoing radical cystectomy.

Nersesyan A, Kundi M, Fenech M, et al.
Micronucleus assay with urine derived cells (UDC): a review of its application in human studies investigating genotoxin exposure and bladder cancer risk.
Mutat Res Rev Mutat Res. 2014 Oct-Dec; 762:37-51 [PubMed] Related Publications
The first micronucleus (MN) study with urine derived cells (UDC) appeared 30 years ago. So far, 56 investigations have been published with this method and it was shown that it can be used for the detection of chromosomal damage caused by environmental and lifestyle factors as well as by occupational exposures and certain diseases This approach may be also useful as a diagnostic tool for the detection and prognosis of bladder cancer. The test system has been improved in the last years, i.e., it was shown that, apart from MN also other nuclear anomalies can be evaluated in UDC which are found in other types of epithelial cells as well (e.g., in oral and nasal cells) and are indicative for acute toxicity (pyknosis, karyorrhexis, karyolysis, condensed chromatin) and genomic instability (nuclear buds, binucleates). Furthermore, an improved protocol with Carnoy I fixation and Papanicolaou stain was developed which enables the discrimination between cells which originate from the cervix and those from the urothelium. The evaluation of the currently available results indicates that exposures and health conditions which are associated with increased cancer rates in the bladder (and possibly also in other organs) lead to positive results in MN-UDC assays and a limited number of studies indicate that this method may be equally sensitive as other more frequently used human biomonitoring assays. The major shortcoming of the UDC-MN method is the lack of standardization; the evaluation of the current data shows that a variety of staining and fixation methods are used and that the numbers of evaluated cells vary over a broad range. These inconsistencies may account for the large inter-laboratory variations of the background frequencies. In order to improve the reliability of the method, further standardization and validation is required. Therefore an international program should be initiated in which a similar strategy could be used as in previous validation/standardization projects concerning MN-cytome assays with lymphocytes and buccal cells.

Kurtova AV, Xiao J, Mo Q, et al.
Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance.
Nature. 2015; 517(7533):209-13 [PubMed] Related Publications
Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.

Related: Apoptosis COX2 (PTGS2) Signal Transduction

Schiffmann J, Gandaglia G, Larcher A, et al.
Contemporary 90-day mortality rates after radical cystectomy in the elderly.
Eur J Surg Oncol. 2014; 40(12):1738-45 [PubMed] Related Publications
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.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter USA

Tian W, Guner G, Miyamoto H, et al.
Utility of uroplakin II expression as a marker of urothelial carcinoma.
Hum Pathol. 2015; 46(1):58-64 [PubMed] Related Publications
Uroplakins are markers of terminally differentiated urothelium. Uroplakin II (UPII) is a newly described sensitive marker for urothelial carcinoma (UC). The expression profile of UPII in different types of UC and its utility in the diagnostic setting are needed. We evaluated UPII expression in bladder tissue microarrays, including urothelial neoplasm of low malignant potential (n = 8), low-grade papillary UC (n = 72), noninvasive high-grade papillary UC (n = 77), UC in situ (n = 27), and invasive high-grade UC (INVUC) (n = 122). UPII expression in 52 breast carcinomas and 38 high-grade prostate adenocarcinomas was also assessed. UPII expression was compared with GATA binding protein 3 (GATA3) and estrogen receptor for its role in facilitating the differential diagnosis of the above 3 types of malignancy. UPII labeling was seen in 83.0% of UC overall, including 95.7% of noninvasive UC and 65.6% of INVUC. UPII labeling was not found in any breast and prostate carcinomas. In comparison, GATA3 labeling was seen in 91.6% of all UCs, including 96.4% of noninvasive UCs and 85.1% of INVUC, with stronger intensity and extent compared with UPII (P < .005). GATA3 labeled 2 (5%) of 38 high-grade prostate adenocarcinoma. Estrogen receptor nuclear labeling was seen in 13.0% of UCs and 12.5% of prostate carcinomas. UPII was highly specific (100%) but only moderately sensitive for UC and can therefore be a potentially useful marker to identify urothelial lineage and help distinguish UC from prostate cancer or, in conjunction with GATA3, from metastatic breast cancer.

Related: Breast Cancer GATA3 gene Prostate Cancer

Wang C, Chen Z, Ge Q, et al.
Up-regulation of p21(WAF1/CIP1) by miRNAs and its implications in bladder cancer cells.
FEBS Lett. 2014; 588(24):4654-64 [PubMed] Related Publications
We have previously reported that synthetic dsRNA can activate p21 expression by targeting the p21 promoter, thereby suppressing the proliferation of human bladder cancer cells. As complementarity between dsRNA and its target sequences is necessary for RNA activation, miRNAs may also trigger p21 expression through the same mechanism. Here, the expression levels of three miRNAs (miR-370, miR-1180 and miR-1236) decreased in bladder cancer tissues compared to healthy controls and the levels of these mRNAs positively correlated with p21 mRNA levels. The three miRNAs induced nuclear p21 expression through p21-promoter binding. Overexpression of the three miRNAs inhibited the proliferation of bladder cancer cells mainly by regulating p21. Therefore, these miRNAs could be candidates for anti-cancer drugs.

Related: Apoptosis CDKN1A MicroRNAs

Angulo JC, Cáceres F, Cabrera PM, et al.
Two-port laparoscopic radical cystectomy with reusable umbilical system: a feasibility study.
Urology. 2014; 84(5):1088-93 [PubMed] Related Publications
OBJECTIVE: To describe the technique and report outcomes of laparoscopic radical cystectomy using 2 ports (2-port LRC) for muscle-invasive bladder cancer.
PATIENTS AND METHODS: Prospective study was performed between November 2011 and October 2012 to standardize 2-port LRC, lymph node dissection, and urinary diversion. Twenty patients were intervened (8 ileal conduit, 12 neobladder) and followed up for >1 yr. Median follow-up was 75.5 weeks (interquartile range, 65.2-86 weeks). A reusable system placed through the umbilicus and laparoscopic curved instruments with double rotation, plus one 10-mm extra port placed in the right iliac fossa were used. Neobladder or conduit was performed extracorporeally. Preoperative, perioperative, and pathologic outcomes and long-term security data are presented.
RESULTS: Median age was 69.5 years; body mass index, 27.4 kg/m(2); operative time, 335 minutes; estimated blood loss, 337 mL; hospital stay, 9 days; intraoperative transfusion rate, 10%; and visual analog pain score, 3 at day 3. Surgical margin was positive in a case (5%); 3 (15%) were pT0, 2 (10%) pT1, 5 (25%) pT2, 6 (30%) pT3a, 3 (15%) pT3b, and 1 (5%) pT4. The number of nodes removed was 18.5 (interquartile range, 16-29.2), 4 (20%) positive. Complications were major in 2 (10%; fecal peritonitis and urinary sepsis) and minor in 4 (20%; ileus and 3 postoperative transfusion) cases. No case required additional analgesia. Incision was totally hidden in the umbilicus. Continence rate in neobladders was 91.7% at daytime and 75% at nighttime. Study limitation was the absence of a comparative cohort.
CONCLUSION: Umbilical 2-port LRC is feasible with good oncologic and functional outcomes, low postoperative pain, and absence of abdominal wall complications. Difficulties have slowed laparoendoscopic single-site radical cystectomy, but umbilical 2-port LRC is a very acceptable alternative for minimally invasive surgery of muscle-invasive bladder cancer.

Siemens DR, Mackillop WJ, Peng Y, et al.
Processes of care and the impact of surgical volumes on cancer-specific survival: a population-based study in bladder cancer.
Urology. 2014; 84(5):1049-57 [PubMed] Related Publications
OBJECTIVE: To describe the relationships between procedure volume and late survival after cystectomy for muscle-invasive bladder cancer (MIBC) and explore variables explaining any effect.
MATERIALS AND METHODS: Electronic records of treatment and surgical pathology reports were linked to a population-based registry to identify patients who underwent cystectomy during 1994-2008 in Ontario, Canada. Explanatory variables included adjuvant chemotherapy, lymph node dissection (LND), and margin status. A Cox proportional hazards regression model was used to explore associations between volume and cancer-specific survival (CSS) as well as overall survival.
RESULTS: The cohort included 2802 MIBC patients treated with cystectomy. High-volume hospitals were more likely to have used adjuvant chemotherapy (25% vs 18%; P <.001), more likely to have performed an LND (83% vs 53%; P <.001), and associated with a lower 90-day mortality (6% vs 10%; P = .032). Low-volume hospitals had a lower 5-year CSS rate of 32% (28%-36%) compared with those of high-volume centers at 38% (33%-42%). Individual surgeon volume was similarly associated with both early- and long-term outcomes. In multivariate analysis, both surgeon and hospital volumes were associated with CSS and overall survival. The surgeon volume effect on long-term outcomes was modestly modified by indicators of the quality of the LND, with little effect of the other explanatory variables.
CONCLUSION: Higher provider volume is associated with higher CSS in patients with MIBC in the general population. The volume effect was modestly mediated by the quality of LND.

Hautmann RE, Abol-Enein H, Lee CT, et al.
Urinary diversion: how experts divert.
Urology. 2015; 85(1):233-8 [PubMed] Related Publications
OBJECTIVE: To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based).
METHODS: Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report.
RESULTS: The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice.
CONCLUSION: Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.

Related: USA

Powles T, Eder JP, Fine GD, et al.
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.
Nature. 2014; 515(7528):558-62 [PubMed] Related Publications
There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.

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Charlton ME, Adamo MP, Sun L, Deorah S
Bladder cancer collaborative stage variables and their data quality, usage, and clinical implications: a review of SEER data, 2004-2010.
Cancer. 2014; 120 Suppl 23:3815-25 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Several changes were made to bladder cancer staging guidelines between the 6th and 7th editions of the American Joint Committee on Cancer (AJCC) Staging Manual. Also, Collaborative Stage (CS) Data Collection System version 2 (CSv2) implemented for 2010 Surveillance, Epidemiology, and End Results (SEER) cases involved collection of 3 new site-specific factors (SSFs): World Health Organization/International Society of Urological pathology grade (SSF1), size of metastasis in regional lymph nodes (SSF2), and extranodal extension (SSF3). Our objective was to evaluate these new SSFs to assist researchers in their use/interpretation and to describe data quality issues to be addressed moving forward.
METHODS: Staging trends were assessed for invasive and noninvasive bladder cancer cases from 2004 to 2010. Among 2010 cases, staging was compared using the AJCC 6th and 7th edition guidelines, and evaluation of completeness/quality of the SSFs was performed in relevant subgroups.
RESULTS: Age-adjusted incidence rates and proportions of cases by stage remained steady from 2004 to 2010. Changes from the AJCC 6th to 7th editions caused no substantial movement between stages. SSF1 had a known value in 82% of cases, which was higher than the traditional SEER grade/differentiation variable. SSF2 and SSF3 were less complete, with 41% and 37% having known values, respectively, among cases with lymph node involvement (according to CS lymph node variable).
CONCLUSIONS: SSF1 was more complete and straightforward to interpret than the traditional grade/differentiation variable. SSF2 and SSF3 were less complete, may be associated with data quality issues, and should only be used among cases with known lymph node involvement.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Pérez-Jacoiste Asín MA, Fernández-Ruiz M, López-Medrano F, et al.
Bacillus Calmette-Guérin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: incidence, risk factors, and outcome in a single-institution series and review of the literature.
Medicine (Baltimore). 2014; 93(17):236-54 [PubMed] Related Publications
Bacillus Calmette-Guérin (BCG) is the most effective intravesical immunotherapy for superficial bladder cancer. Although generally well tolerated, BCG-related infectious complications may occur following instillation. Much of the current knowledge about this complication comes from single case reports, with heterogeneous diagnostic and therapeutic approaches and no investigation on risk factors for its occurrence. We retrospectively analyzed 256 patients treated with intravesical BCG in our institution during a 6-year period, with a minimum follow-up of 6 months after the last instillation. We also conducted a comprehensive review and pooled analysis of additional cases reported in the literature since 1975. Eleven patients (4.3%) developed systemic BCG infection in our institution, with miliary tuberculosis as the most common form (6 cases). A 3-drug antituberculosis regimen was initiated in all but 1 patient, with a favorable outcome in 9/10 cases. There were no significant differences in the mean number of transurethral resections prior to the first instillation, the time interval between both procedures, the overall mean number of instillations, or the presence of underlying immunosuppression between patients with or without BCG infection. We included 282 patients in the pooled analysis (271 from the literature and 11 from our institution). Disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections were the most common presentations of disease. Specimens for microbiologic diagnosis were obtained in 87.2% of cases, and the diagnostic performances for acid-fast staining, conventional culture, and polymerase chain reaction (PCR)-based assays were 25.3%, 40.9%, and 41.8%, respectively. Most patients (82.5%) received antituberculosis therapy for a median of 6.0 (interquartile range: 4.0-9.0) months. Patients with disseminated infection more commonly received antituberculosis therapy and adjuvant corticosteroids, whereas those with reactive arthritis were frequently treated only with nonsteroidal antiinflammatory drugs (p < 0.001 for all comparisons). Attributable mortality was higher for patients aged ≥65 years (7.4% vs 2.1%; p = 0.091) and those with disseminated infection (9.9% vs 3.0%; p = 0.040) and vascular involvement (16.7% vs 4.6%; p = 0.064). The scheduled BCG regimen was resumed in only 2 of 36 patients with available data (5.6%), with an uneventful outcome. In the absence of an apparent predictor of the development of disseminated BCG infection after intravesical therapy, and considering the protean variety of clinical manifestations, it is essential to keep a high index of suspicion to initiate adequate therapy promptly and to evaluate carefully the risk-benefit balance of resuming intravesical BCG immunotherapy.

Li W, Liang Y, Deavers MT, et al.
Uroplakin II is a more sensitive immunohistochemical marker than uroplakin III in urothelial carcinoma and its variants.
Am J Clin Pathol. 2014; 142(6):864-71 [PubMed] Related Publications
OBJECTIVES: Uroplakin (UP) II and UPIII are highly specific immunohistochemical markers for urothelial differentiation. Here we studied the sensitivity of UPII and UPIII in conventional and variant urothelial carcinomas (UCs).
METHODS: Immunohistochemical staining for UPII and UPIII was performed on tissue microarray slides, including 105 conventional bladder UCs (BUCs), 90 upper urinary tract UCs (UUTUCs), and 47 micropapillary, 16 plasmacytoid, 22 small cell carcinoma, and 41 sarcomatoid UC variants.
RESULTS: UPII expression was significantly higher than UPIII expression in conventional BUC (44% vs 17%, P < .001) and UUTUC (67% vs 46%, P = .045). UPIII expression was significantly higher in UUTUC than in BUC (P < .001). In UC variants, UPII expression was significantly higher than UPIII expression in micropapillary (91% vs 25%, P < .001), plasmacytoid (63% vs 6%, P < .001), and sarcomatoid (29% vs 5%, P = .032) variants. Only rare cases of the small cell carcinoma variant had focal UPII and UPIII expression. Compared with conventional UC, the sarcomatoid variant had significantly lower UPII expression, whereas the micropapillary variant had significantly higher UPII expression (P < .001).
CONCLUSIONS: UPII demonstrates a significantly higher sensitivity than UPIII in conventional and variant UCs. Thus, UPII is a more valuable marker than UPIII in immunohistochemical analyses for confirming the urothelial origin of carcinomas.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Shiels MS, Gibson T, Sampson J, et al.
Cigarette smoking prior to first cancer and risk of second smoking-associated cancers among survivors of bladder, kidney, head and neck, and stage I lung cancers.
J Clin Oncol. 2014; 32(35):3989-95 [PubMed] Article available free on PMC after 10/12/2015 Related Publications
PURPOSE: Data on smoking and second cancer risk among cancer survivors are limited. We assessed associations between smoking before first cancer diagnosis and risk of second primary smoking-associated cancers among survivors of lung (stage I), bladder, kidney, and head/neck cancers.
METHODS: Data were pooled from 2,552 patients with stage I lung cancer, 6,386 with bladder cancer, 3,179 with kidney cancer, and 2,967 with head/neck cancer from five cohort studies. We assessed the association between prediagnostic smoking and second smoking-associated cancer risk with proportional hazards regression, and compared these estimates to those for first smoking-associated cancers in all cohort participants.
RESULTS: Compared with never smoking, current smoking of ≥ 20 cigarettes per day was associated with increased second smoking-associated cancer risk among survivors of stage I lung (hazard ratio [HR] = 3.26; 95% CI, 0.92 to 11.6), bladder (HR = 3.67; 95% CI, 2.25 to 5.99), head/neck (HR = 4.45; 95% CI, 2.56 to 7.73), and kidney cancers (HR = 5.33; 95% CI, 2.55 to 11.1). These estimates were similar to those for first smoking-associated cancer among all cohort participants (HR = 5.41; 95% CI, 5.23 to 5.61). The 5-year cumulative incidence of second smoking-associated cancers ranged from 3% to 8% in this group of cancer survivors.
CONCLUSION: Understanding risk factors for second cancers among cancer survivors is crucial. Our data indicate that cigarette smoking before first cancer diagnosis increases second cancer risk among cancer survivors, and elevated cancer risk in these survivors is likely due to increased smoking prevalence. The high 5-year cumulative risks of smoking-associated cancers among current smoking survivors of stage I lung, bladder, kidney, and head/neck cancers highlight the importance of smoking cessation in patients with cancer.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Kidney Cancer Lung Cancer Smoking and Smoking Cessation

Bassett JC, Gore JL, Kwan L, et al.
Knowledge of the harms of tobacco use among patients with bladder cancer.
Cancer. 2014; 120(24):3914-22 [PubMed] Related Publications
BACKGROUND: The objective of this study was to determine tobacco use knowledge and attribution of cause in patients with newly diagnosed bladder cancer.
METHODS: A stratified, random sample of bladder cancer survivors diagnosed between 2006 and 2009 was obtained from the California Cancer Registry. Respondents were surveyed about tobacco use, risk factors, and sources of information on the causes of bladder cancer. Contingency tables and logistic regression analyses were used to evaluate tobacco use knowledge and beliefs.
RESULTS: Of 1198 eligible participants, 790 (66%) completed the survey. Sixty-eight percent of the cohort had a history of tobacco use, and 19% were active smokers at diagnosis. Tobacco use was the most cited risk factor for bladder cancer, with active smokers more knowledgeable than former smokers or never smokers (90% vs 64% vs 61%, respectively; P<.001). Urologists were the predominant source of information and were cited most often by active smokers (82%). In multivariate analyses, active smokers had 6.37 times greater odds (95% confidence interval, 3.35-12.09) than never smokers of endorsing tobacco use as a risk factor for bladder cancer, and smokers who named the urologist as their information source had 2.80 times greater odds (95% confidence interval, 1.77-4.43) of believing tobacco use caused their cancer.
CONCLUSIONS: Patients' smoking status and primary source of information were associated with knowledge of the harms of tobacco use and, in smokers, acknowledgment that tobacco use increased the risk of their own disease. Urologists play a critical role in ensuring patients' knowledge of the connection between smoking and bladder cancer, particularly for active smokers who may be motivated to quit.

Related: Smoking and Smoking Cessation

Klopfer K, Delahunt B, Adamson M, Samaratunga H
Value of uroplakin III in distinguishing variants of primary bladder urothelial carcinoma from malignancy metastatic to the urinary bladder.
Anticancer Res. 2014; 34(11):6779-84 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) variants can be difficult to differentiate from carcinoma metastatic to the bladder.
MATERIALS AND METHODS: We examined immunostaining for uroplakin III in 43 cases of primary bladder UC variants including micropapillary UC (n=19), nested variant of UC (n=2), pleomorphic giant-cell carcinoma (n=8), plasmacytoid UC (n=4), lymphoepithelioma-like carcinoma (n=2), large cell undifferentiated carcinoma (n=2), UC with abundant myxoid stroma (n=3) and lipid cell variant (n=3) and in 11 tumors from other organs metastatic to the bladder. These tumors included invasive ductal carcinoma of the breast (n=2), colorectal adenocarcinoma (n=4), endometrioid adenocarcinoma (n=1) and serous papillary carcinoma of the uterus (n=1) melanoma (n=1), embryonal carcinoma of the testis (n=1), and renal clear cell carcinoma (n=1).
RESULTS: Out of the 43 UC variants, 35 (81%) were positive for uroplakin III, including micropapillary, lipid cell variant and UC with abundant myxoid stroma. Pleomorphic giant cell carcinoma, plasmacytoid UC and nested variant of UC were less commonly positive. Of the 11 metastatic tumors, six were found to be positive for uropIakin III: metastatic colorectal adenocarcinoma, clear cell carcinoma of the kidney and embryonal carcinoma of testis.
CONCLUSION: UP III Positivity for uroplakin III is not found only in primary bladder UC variants, but in some tumors that have metastatized to the bladder. Staining for uroplakin III alone should not be taken as evidence of UC.

Mak RH, Hunt D, Shipley WU, et al.
Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.
J Clin Oncol. 2014; 32(34):3801-9 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PURPOSE: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies.
PATIENTS AND METHODS: Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method.
RESULTS: The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively.
CONCLUSION: This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.

Sathe A, Guerth F, Cronauer MV, et al.
Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.
Br J Cancer. 2014; 111(11):2103-13 [PubMed] Article available free on PMC after 25/11/2015 Related Publications
BACKGROUND: Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response.
METHODS: Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation.
RESULTS: Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.

Related: Apoptosis AKT1

Mitra AP, Lam LL, Ghadessi M, et al.
Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer.
J Natl Cancer Inst. 2014; 106(11) [PubMed] Article available free on PMC after 25/11/2015 Related Publications
BACKGROUND: Nearly half of muscle-invasive bladder cancer patients succumb to their disease following cystectomy. Selecting candidates for adjuvant therapy is currently based on clinical parameters with limited predictive power. This study aimed to develop and validate genomic-based signatures that can better identify patients at risk for recurrence than clinical models alone.
METHODS: Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. Genomic (GC) and clinical (CC) classifiers for predicting recurrence were developed on a discovery set (n = 133). Performances of GC, CC, an independent clinical nomogram (IBCNC), and genomic-clinicopathologic classifiers (G-CC, G-IBCNC) were assessed in the discovery and independent validation (n = 66) sets. GC was further validated on four external datasets (n = 341). Discrimination and prognostic abilities of classifiers were compared using area under receiver-operating characteristic curves (AUCs). All statistical tests were two-sided.
RESULTS: A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. This was higher than individual clinical variables, IBCNC (AUC = 0.73), and comparable to CC (AUC = 0.78). Performance was improved upon combining GC with clinical nomograms (G-IBCNC, AUC = 0.82; G-CC, AUC = 0.86). G-CC high-risk patients had elevated recurrence probabilities (P < .001), with GC being the best predictor by multivariable analysis (P = .005). Genomic-clinicopathologic classifiers outperformed clinical nomograms by decision curve and reclassification analyses. GC performed the best in validation compared with seven prior signatures. GC markers remained prognostic across four independent datasets.
CONCLUSIONS: The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This may be used to better identify patients who need more aggressive management.

Kim JY, Kim SH, Lee HJ, et al.
MDCT urography for detecting recurrence after transurethral resection of bladder cancer: comparison of nephrographic phase with pyelographic phase.
AJR Am J Roentgenol. 2014; 203(5):1021-7 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to prospectively compare nephrographic phase MDCT urography performed with oral hydration and a diuretic with standard pyelographic phase MDCT in the detection of recurrence after transurethral resection.
SUBJECTS AND METHODS: The study included 140 MDCT urographic examinations of 121 patients (87 men, 34 women; age range, 46-88 years) at risk of urinary tract cancer recurrence. Acquisition was performed 60 seconds (nephrographic phase) and 420 seconds (pyelographic phase) after contrast injection. Two radiologists independently recorded the presence of recurrent lesions in each phase. The reference standard was histologic findings and prospective clinical decision. Distention and opacification were compared for each radiologist in each segment in each phase by kappa statistic and Spearman rank coefficient. Generalized estimating equations for logistic regression analysis were used to compare performance for each radiologist and phase and were adjusted for possibility within patient correlation.
RESULTS: Urinary tract distention was rated significantly better at the pyelographic phase for all segments (p < 0.001). The degree of opacification provided by each radiologist for the same segment showed high correlation. There were 59 bladder recurrences in 38 patients and 19 upper tract recurrences in 13 patients. For recurrence detection in the bladder, the overall accuracy was significantly higher for the nephrographic phase than the pyelo-graphic phase (91.7% [354/386] vs 83.2% [321/386], p = 0.038). For recurrence detection in the upper tract, the overall accuracy was significantly higher in the nephrographic phase than in the pyelographic phase (86.7% [260/300] vs 80% [240/300], p = 0.028).
CONCLUSION: Use of nephrographic phase MDCT urography is associated with a higher rate of detection of urinary tract recurrence than is pyelographic phase MDCT, which suggests the value of this technique for evaluating the urinary tract after transurethral resection.

McNeil BK, Sorbellini M, Grubb RL, et al.
Preliminary evaluation of urinary soluble Met as a biomarker for urothelial carcinoma of the bladder.
J Transl Med. 2014; 12:199 [PubMed] Article available free on PMC after 25/11/2015 Related Publications
BACKGROUND: Among genitourinary malignancies, bladder cancer (BCa) ranks second in both prevalence and cause of death. Biomarkers of BCa for diagnosis, prognosis and disease surveillance could potentially help prevent progression, improve survival rates and reduce health care costs. Among several oncogenic signaling pathways implicated in BCa progression is that of hepatocyte growth factor (HGF) and its cell surface receptor, Met, now targeted by 25 experimental anti-cancer agents in human clinical trials. The involvement of this pathway in several cancers is likely to preclude the use of urinary soluble Met (sMet), which has been correlated with malignancy, for initial BCa screening. However, its potential utility as an aid to disease surveillance and to identify patients likely to benefit from HGF/Met-targeted therapies provide the rationale for this preliminary retrospective study comparing sMet levels between benign conditions and primary BCa, and in BCa cases, between different disease stages.
METHODS: Normally voided urine samples were collected from patients with BCa (Total: 183; pTa: 55, pTis: 62, pT1: 24, pT2: 42) and without BCa (Total: 83) on tissue-procurement protocols at three institutions and sMet was measured and normalized to urinary creatinine. Normalized sMet values grouped by pathologic stage were compared using non-parametric tests for correlation and significant difference. ROC analyses were used to derive classification models for patients with or without BCa and patients with or without muscle-invasive BCa (MIBCa or NMIBCa).
RESULTS: Urinary sMet levels accurately distinguished patients with BCa from those without (p<0.0001, area under the curve (AUC): 0.7008) with limited sensitivity (61%) and moderate specificity (76%), and patients with MIBCa (n=42) from those with NMIBCa (n=141; p<0.0001, AUC: 0.8002) with moderate sensitivity and specificity (76% and 77%, respectively) and low false negative rate (8%).
CONCLUSIONS: Urinary sMet levels distinguish patients with BCa from those without, and patients with or without MIBCa, suggesting the potential utility of urinary sMet as a BCa biomarker for surveillance following initial treatment. Further studies are warranted to determine its potential value for prognosis in advanced disease, predicting treatment response, or identifying patients likely to benefit from Met-targeted therapies.

Related: MET gene

Davydov MI, Akchurin RS, Gerasimov SS, et al.
Surgical treatment of patients with kidney and bladder cancer in case of severe concomitant cardiovascular diseases.
Khirurgiia (Mosk). 2014; (9):4-16 [PubMed] Related Publications
It was operated 17 patients with kidney and bladder cancer against the background of severe concomitant coronary artery disease (52.9%), aortic aneurysm (35.3%) or combination of coronary artery disease with Leriche syndrome (5.9%) or hemodynamically significant stenosis of internal carotid artery (5.9%). Patients were operated for the period from 1998 to 2012. All patients were male at the age from 39 to 80 years (mean 62.1 years). The first stage of kidney cancer was diagnosed in 8 (53.3%) patients, the second stage - in 1 (6.7%) patient, the third stage - in 2 (13.3%) patients and the fourth stage was observed in 4 (26.7%) patients. Bladder cancer had 1 and 2 stages. Simultaneous operations were performed in 3 (17.6%) patients. 12 (70.6%) patients were operated consequentially. Surgery for kidney cancer was not done in 2 (11.8%) of 17 patients because of patient death after coronary bypass surgery or patient refusal of surgery after carotid arteries stenting. Intraoperative and postoperative complications have been developed in 9 (52.9%) of 17 patients. 2 (11.8%) patients died. The complications frequency and mortality after simultaneous operations were 25% (1 of 4) and 0. These parameters were 57.1% (8 of 14) and 14.3% respectively in case of consequent tactics. It was not observed myocardial infarction and aortic aneurysm rupture after surgeries for kidney and bladder cancer. Overall 1, 3, 5 - year survival of patients with kidney cancer and severe concomitant cardiovascular diseases was 100%, 73.3% and 52.4% respectively. It was concluded that surgical treatment of severe concomitant coronary artery disease and aortic aneurysm in patients with kidney and bladder cancer decreases risk of myocardial infarction and aortic aneurysm rupture in intraoperative and postoperative periods.

Related: Kidney Cancer

Bertz S, Abeé C, Schwarz-Furlan S, et al.
Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer.
Virchows Arch. 2014; 465(6):687-95 [PubMed] Related Publications
Compared to other members of the fibroblast growth factor receptor (FGFR) family, only few studies investigate FGFR3 in tumour angiogenesis. We investigated the connection between angiogenesis and FGF/FGFR expression including FGFR3 mutation status in urothelial carcinomas. Immunohistochemistry was performed in invasive and non-invasive urothelial cancers of 61 patients. Protein expression of CD31, factor VIII (FVIII), FGF-1/2, FGFR1, FGFR3 and FGFR4 and FGFR3 mutation status were evaluated. Morphometric assessment of angiogenesis including microvessel count (MVC) and vascular surface area (VSA) was analysed. Correlation and survival analyses (overall survival (OS) and disease-free survival (DFS)) with univariate and multivariate analyses were performed. CD31 values (MVC and VSA) significantly correlated with OS and DFS. OS and DFS were significantly better in patients with FGFR3 overexpression. Multivariate analysis revealed FGFR3 protein expression and tumour grading (WHO classification 2004) as independent prognostic factors of OS and VSA of CD31 and FGFR3 protein expression of DFS. FGFR3 mutation status was correlated with VSA measured by FVIII. FGFR3 may be able to induce a pro-angiogenic phenotype in urothelial carcinomas and significantly influence prognosis. Consequently, FGFR3 is a potential therapeutic target also from the angiogenesis perspective.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Angiogenesis and Cancer

Fu YP, Kohaar I, Moore LE, et al.
The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.
Cancer Res. 2014; 74(20):5808-18 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

Related: Chromosome 19 CCNE1

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