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Neoadjuvant or adjuvant chemotherapy: what is the best treatment of muscle invasive bladder cancer?
Nabil Ismaili,Sanaa Elmajjaoui,Youssef Bensouda,Rhizlane Belbaraka
Oncology Reviews , 2011, DOI: 10.4081/33
Abstract: Bladder cancer is the fourth most common cancer for men and the eighth most common cancer for women. Transitional cell carcinoma is the most predominant histological type. Bladder cancer is highly chemosensitive. In metastatic setting the treatment is based on cisplatin chemotherapy regimens type MVAC, MVAC-HD or gemcitabine plus cisplatin. The standard treatment of muscle invasive operable bladder cancer (T2–T4) used widely was radical cystectomy with pelvic lymph nodes dissection; the anatomical extent of pelvic lymphadenectomy has not accurately been defined so far. However, in the last decade, the treatment of tumors was improved by the introduction of chemotherapy as part of the management of the disease. Neoadjuvant chemotherapy should be considered at first, as standard treatment of choice, before local treatment for patients with good performance status (0–1) and good renal function–glomerular filtration rate (GFR) >60 mL/min. For patients treated with primary surgery, adjuvant chemotherapy is a valuable option in the case of lymph nodes involvement. This brief review would provide the evidence of the role of neoadjuvant chemotherapy in the management of operable muscle invasive (T2–T4) bladder cancer.
Identification of C16orf74 as a Marker of Progression in Primary Non-Muscle Invasive Bladder Cancer  [PDF]
Won Tae Kim,Seok Joong Yun,Cheol Park,Isaac Yi Kim,Sung-Kwon Moon,Tae Gyun Kwon,Yung Hyun Choi,Wun-Jae Kim
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015260
Abstract: Methylation-induced silencing of PRSS3 has been shown to be significantly associated with invasive bladder cancer, and expression of the C16orf74 gene locus has been shown to correlate positively with PRSS3. The aim of the current study was to evaluate the relationship between C16orf74 expression level and progression in non-muscle invasive bladder cancer (NMIBC).
Proteomics research on muscle-invasive bladder transitional cell carcinoma
Hai Niu, Zhen Dong, Gang Jiang, Ting Xu, Yan Liu, Yan Cao, Jun Zhao, Xin Wang
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-17
Abstract: A total of 885/890 proteins commonly appeared in 4 paired samples. 295/337 of the 488/493 proteins that specific expressed in tumor/normal cells own gene ontology (GO) cellular component annotation. Compared with the entire list of the international protein index (IPI), there are 42/45 GO terms exhibited as enriched and 9/5 exhibited as depleted, respectively. Several pathways exhibit significantly changes between cancer and normal cells, mainly including spliceosome, endocytosis, oxidative phosphorylation, etc. Finally, descriptive statistics show that the PI Distribution of candidate biomarkers have certain regularity.The present study identified the proteome expression profile of muscle-invasive bladder cancer cells and normal urothelial cells, providing information for subcellular pattern research of cancer and offer candidate proteins for biomarker panel and network-based multi-target therapy.Despite elaborate characterization of the risk factors, muscle-invasive bladder transitional cell carcinoma (BTCC) is still a major epidemiological problem whose incidence continues to rise each year [1]. The standard therapeutic methods of muscle-invasive BTCC are radical cystectomy (RC) followed postoperative care. Though there are much progress in surgical techniques and perioperative chemoradiation, the 5-year disease specific survival after RC remains 50-60% [2]. At present, the detailed mechanism for the carcinogenesis and development of invasive bladder carcinoma remains to be elucidated.Though there were several proteomics research on muscle-invasive BTCC and make certain progress, the achievement of these researches were confined by the limited proteins identified from cancer tissue [3-5]. Nowadays, sophisticated proteomic, computational, and statistical tools offer us increased possibility of assimilating existing data to discover cancer biology and develop effective biomarkers for diagnosis and targeted therapy [6]. Meanwhile, with these technologies, some new c
Stromal proteome expression profile and muscle-invasive bladder cancer research
Haitao Niu, Haiping Jiang, Bo Cheng, Xinhui Li, Qian Dong, Leping Shao, Shiguo Liu, Xinsheng Wang
Cancer Cell International , 2012, DOI: 10.1186/1475-2867-12-39
Abstract: We identified 868/872 commonly expressed proteins and 978 differential proteins from 4 paired cancer and normal stromal samples using laser capture micro dissection coupled with two-dimensional liquid chromatography tandem mass spectrometry. 487/491 proteins uniquely expressed in cancer/normal stroma. Differential proteins were compared with the entire list of the international protein index (IPI), and there were 42/42 gene ontology (GO) terms exhibited as enriched and 8/5 exhibited as depleted in cellular Component, respectively. Significantly altered pathways between cancer/normal stroma mainly include metabolic pathways, ribosome, focal adhesion, etc. Finally, descriptive statistics show that the stromal proteins with extremes of PI and MW have the same probability to be a biomarker.Based on our results, stromal cells are essential component of the cancer, biomarker discovery and network based multi target therapy should consider neoplastic cells itself and corresponding stroma as whole one.Despite recent advances in surgical techniques, perioperative chemo radiotherapy and the development of molecularly targeted therapies, muscle-invasive bladder transitional cell carcinoma (BTCC) is still a major epidemiological problem whose incidence continues to rise each year [1]. The prognosis of muscle-invasive BTCC is poor and the 5-year disease specific survival after radical cystectomy remains 50–60% [2]. Though some molecular pathogenesis studies on invasive bladder carcinoma have been undertaken successfully on the gene and transcription levels, the carcinogenic mechanism remains to be elucidated. In this regard, using stroma as a sample may be an alterative way to study muscle-invasive BTCC carcinogenesis. However, there has been no report of this item.As one of the solid tumors, muscle-invasive BTCC are composed of two independent while interactive components: the neoplastic epithelial cells and the surrounding cancer stroma. These two components interactive and in
Molecular Assessment of Non-Muscle Invasive and Muscle Invasive Bladder Tumors: Mapping of Putative Urothelial Stem Cells and Toll-Like Receptors (TLR) Signaling  [PDF]
Rafael Mamprin Stopiglia, Wagner Eduardo Matheus, Patrick Vianna Garcia, Athanase Billis, Mariana Anteghini Castilho, Vitor Hugo Figueiredo de Jesus, Ubirajara Ferreira, Wagner José Fávaro
Journal of Cancer Therapy (JCT) , 2015, DOI: 10.4236/jct.2015.62014

Purpose: The main objectives of this study were to characterize and compare the urothelial stem cells (healthy and cancer cells) and TLRs features in the urinary bladder of men without lesionsand with non-muscle-invasive and muscle invasive urothelial tumors. Materials and Methods: Thirty samples of the urinary bladder of 50 to 80-year-old men, with and without diagnosis of malignant urothelial lesions were used. The 30 samples were divided into 3 groups (n = 10 per group): Normal Group; Non-Muscle Invasive Bladder Cancer Group; Muscle Invasive Bladder Cancer Group. The samples were histopathologically and immunohistochemically analyzed. The study was conducted at teaching Hospital of the University of Campinas (UNICAMP). Results: The CD44 and CD133 immunoreactivities were significantly intense in the muscle-invasive cancer group when compared to the other groups. The ABCG2 biomarker demonstrated intense immunoreactivities in both non-muscle and muscle invasive groups, and absent immunoreactivity in the normal group. All groups showed weak CD117 immunoreactivity. Putative Healthy Stem Cells (CD44/CD133/ CD117+) occurred in all groups. Putative Cancer Stem Cells (CD44/CD133/ABCG2+) only occurred in the non-muscle and muscle invasive cancer groups. TLR2 immunoreactivity was significantly lower in the non-muscle invasive cancer group and absent in the muscle invasive cancer group. TLR4 immunoreactivity was significantly lower in both cancer groups. Conclusions: This study leads us to the conclusion that putative cancer stem cell occurrence was sensitive to the decreased in TLR2 and TLR4 immunoreactivities. Also, TLR2 and TLR4 demonstrated their involvement in the regulation of the different biomarkers for putative healthy and cancer urothelial stem cells, probably acting as negative regulators of urothelial carcinogenesis. Taken together data obtained suggest that use of TLRs agonists could be a promising alternative for the treatment of non-muscle and muscle invasive bladder tumors.

Surveillance and Treatment of Non-Muscle-Invasive Bladder Cancer in the USA  [PDF]
Daniel A. Barocas,Denise R. Globe,Danielle C. Colayco,Ahunna Onyenwenyi,Amanda S. Bruno,Thomas J. Bramley,Rachel J. Spear
Advances in Urology , 2012, DOI: 10.1155/2012/421709
Abstract: Seventy percent of newly diagnosed bladder cancers are classified as non-muscle-invasive bladder cancer (NMIBC) and are often associated with high rates of recurrence that require lifelong surveillance. Currently available treatment options for NMIBC are associated with toxicities that limit their use, and actual practice patterns vary depending upon physician and patient characteristics. In addition, bladder cancer has a high economic and humanistic burden in the United States (US) population and has been cited as one of the most costly cancers to treat. An unmet need exists for new treatment options associated with fewer complications, better patient compliance, and decreased healthcare costs. Increased prevention of recurrence through greater adherence to evidence-based guidelines and the development of novel therapies could therefore result in substantial savings to the healthcare system. 1. Introduction Non-muscle-invasive bladder cancer (NMIBC), formerly known as superficial bladder cancer, is a common, heterogeneous disease associated with high rates of recurrence and that often requires lifelong surveillance [1–4]. Treatment options for NMIBC are limited, with initial management involving transurethral resection of the bladder tumor (TURBT), followed by adjuvant instillations of chemotherapy or immunotherapy to reduce recurrence rates and prevent disease progression [3]. Commonly used current intravesical therapies include mitomycin C—a naturally occurring product of Streptomyces bacteria that has antibacterial and antitumor properties—and bacillus Calmette-Guérin (BCG), an attenuated mycobacterium that produces an inflammatory reaction in the bladder. Both of these therapies were introduced several decades ago and have been shown to reduce recurrence rates. Each of the intravesical therapy options has associated toxicities that can impair patient compliance, particularly so for BCG, which routinely causes irritative voiding symptoms, often causes fever and malaise, and in rare cases, results in systemic sepsis [5–9]. Clinical guidelines for NMIBC aim to guide clinicians to appropriate use of intravesical therapy; however, guidelines from the different associations vary in their recommendations, so the physician’s subjective assessment of the benefits and the patient’s preferences (such as acceptability of risk) can supersede the available evidence favoring the use of intravesical therapy [10–16]. As a result, real-world utilization of intravesical therapy often falls below the recommendations, resulting in potentially preventable bladder cancer
The role of partial cystectomy in treatment of muscle invasive bladder cancer
Vukoti? V.,Lazi? M.,Savi? S.,Cerovi? S.
Acta Chirurgica Iugoslavica , 2007, DOI: 10.2298/aci0704025v
Abstract: Muscle invasive bladder cancer is usually treated by radical cystectomy, but in some selected cases with solitary tumor with appropriate localization partial cystectomy can be the treatment of choice achieving long term results with bladder preservation. We reviewed records of 11 patients which were treated in 5 year period from June 2002 to June 2007. by partial cystectomy according to the size of the tumor, localization, histology, multifocality, pathological and clinical stage, sex, and age. Male: female ratio was 6:5, mean age of the patients being 64.9 years. All patients bur one had solitary lesions located in the bladder dome in 4, on lateral sides in 5,2 patients had a tumor in diverticulum. TCC gr II was diagnosed 6 pts, TCC gr III in 5. One patient died in a year from disease progression, one from other reason, while all other patients are alive and disease free, the longest disease free interval being 3 years. Bladder capacity is adequate in all patients resulting in good quality of life .Our results suggest that in selected patients cancer control can be achieved with partial cystectomy.
p63 Expression Defines a Lethal Subset of Muscle-Invasive Bladder Cancers  [PDF]
Woonyoung Choi, Jay B. Shah, Mai Tran, Robert Svatek, Lauren Marquis, I-Ling Lee, Dasom Yu, Liana Adam, Sijin Wen, Yu Shen, Colin Dinney, David J. McConkey, Arlene Siefker-Radtke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030206
Abstract: Background p63 is a member of the p53 family that has been implicated in maintenance of epithelial stem cell compartments. Previous studies demonstrated that p63 is downregulated in muscle-invasive bladder cancers, but the relationship between p63 expression and survival is not clear. Methodology/Principal Findings We used real-time PCR to characterize p63 expression and several genes implicated in epithelial-to-mesenchymal transition (EMT) in human bladder cancer cell lines (n = 15) and primary tumors (n = 101). We correlated tumor marker expression with stage, disease-specific (DSS), and overall survival (OS). Expression of E-cadherin and p63 correlated directly with one another and inversely with expression of the mesenchymal markers Zeb-1, Zeb-2, and vimentin. Non-muscle-invasive (Ta and T1) bladder cancers uniformly expressed high levels of E-cadherin and p63 and low levels of the mesenchymal markers. Interestingly, a subset of muscle-invasive (T2–T4) tumors maintained high levels of E-cadherin and p63 expression. As expected, there was a strongly significant correlation between EMT marker expression and muscle invasion (p<0.0001). However, OS was shorter in patients with muscle-invasive tumors that retained p63 (p = 0.007). Conclusions/Significance Our data confirm that molecular markers of EMT are elevated in muscle-invasive bladder cancers, but interestingly, retention of the “epithelial” marker p63 in muscle-invasive tumors is associated with a worse outcome.
Evaluation of tissue and urinary survivin expression in non-muscle-invasive bladder cancer
S Sharaf, A Ketat, I Diab, F Dwidar, W Sameh
African Journal of Urology , 2012,
Abstract: Introduction: Approximately 70% of bladder cancers are non-muscle-invasive (NMIBC), and respond well to endoscopic transurethral resection. However, 70% of these patients experience tumor recurrence. As the tendency for local recurrence and/or progression extends over the lifetime, patients with superficial bladder cancer must undergo life-long surveillance. Combination of cystoscopy and urine cytology is considered the “gold standard” for this surveillance. However, they suffer from drawbacks where cystoscopy is an invasive procedure and urine cytology shows limited ability to detect low grade bladder tumors. Therefore, new non-invasive tests with high sensitivity and specificity that are easy to perform are needed not only for initial diagnosis but also in surveillance for recurrent tumors. Objective: To investigate the magnitude of survivin expression in non-muscle-invasive bladder cancer and its possible value as a non invasive diagnostic tool. Patients and methods: From March 2010 to October 2010, 68 patients with known history of NMIBC who were scheduled for follow-up cystoscopy in the department of Urology, Alexandria University were included in this study prospectively. All patients underwent cystoscopy under general anaesthesia, and those who were found to have a definite or suspicious lesion(s) in the bladder underwent complete TURBT. Survivin expression was determined in urine and in bladder cancer tissue both by Western blotting and by ELISA. Results: The study included 68 patients. Tumor recurrence was detected in 38 patients, of whom, 24 had low grade recurrence. The urinary concentration of survivin was significantly higher in the recurrence group by both detection methods (U= 141, P = 0.018 and χ2 = 10.46, P = 0.001 for ELISA and WB respectively). Survivin by ELISA showed higher sensitivity and specificity (84.4% and 100%) than that by WB (55.3% and 93.3%). In tumor tissue, by both methods, survivin was detected in higher levels than in urine but there was no significant correlation between urinary and tissue levels neither in the whole recurrence group nor in the low grade subgroup. Conclusion: Urinary survivin is a useful marker for non-invasive detection of non-muscle-invasive bladder cancer recurrence. Its detection is better using ELISA technique thanWBand there is no correlation between its expression in tissue and urine.
Clinical significance of subepithelial growth patterns in non-muscle invasive bladder cancer
Makito Miyake, Shuya Hirao, Hisakazu Mibu, Masahiro Tanaka, Kenji Takashima, Keiji Shimada, Kazuya Hirao
BMC Urology , 2011, DOI: 10.1186/1471-2490-11-17
Abstract: In total, 130 patients newly diagnosed with non-muscle invasive bladder cancer and underwent transurethral resection between 1998 and 2009 were enrolled. Subepithelial growth patterns consisting of endophytic growth pattern (EGP) and von Brunn's nest involvement (VBNI) were investigated using hematoxylin and eosin-stained slides, and their frequency of occurrence, prognostic value, and correlation with other clinicopathological features was evaluated.EGP and VBNI were found in 40 (30.8%) and 5 (3.9%) of the 130 cases, respectively. Of the 26 pT1 tumors, the growth pattern at the invasion front was trabecular in 17 (65.4%) and infiltrative in 9 (34.6%). Although 8 (47.1%) of 17 trabecular tumors coexisted with EGP, no cases with infiltrative tumors had EGP (p = 0.023). VBNI correlated with high tumor grades (p = 0.006) and lymphovascular involvement (p = 0.026). The multivariate Cox proportional hazards analysis revealed that tumor diameter less than 3 cm (p = 0.04) and intravesical bacillus Calmette-Guérin therapy (p = 0.004) were independent favorable prognostic factors for recurrence-free survival, whereas tumor stage was an independent poor prognostic factor for disease progression (p = 0.006).Subepithelial growth patterns were not a significant prognostic factor in this study. Additionally, no tumors with an infiltrative growth pattern coexisted with EGP, suggesting that determining the presence of EGP might be helpful for managing non-muscle invasive bladder cancers.Urothelial carcinoma (UC) of the bladder is a malignant neoplasm characterized by heterogenous cell populations and divergent clinical outcomes. Approximately 70% of newly diagnosed bladder cancers are non-muscle invasive bladder cancers (NMIBCs) (pTa-1 or pTis), for which the initial treatment is trans-urethral resection of bladder tumor (TURBT). However, 50-70% of these patients experience intravesical recurrence within 5 years, and almost 10% progress to muscle invasive (≥ pT2) or metastatic dise
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