Urologic Oncology: Seminars and Original Investigations - Articles in Press

Summary of the 6th annual bladder cancer think tank: New directions in urologic research - Corrected Proof

2012-02-02

Abstract: The 6th Annual Bladder Cancer Think Tank brought together a multidisciplinary group of clinicians, researchers, and representatives from the National Cancer Institute and Industry in an effort to advance bladder cancer research efforts. This year's meeting comprised panel discussions and research involving 5 separate working groups, including the Survivorship, Clinical Trials, Standardization of Care, Data Mining, and Translational Science working groups. In this manuscript, the accomplishments and objectives of the working groups are summarized. Notable efforts include: (1) the development of a survivorship care plan for early and late-stage bladder cancer; (2) the development of consensus criteria for eligibility and endpoints for bladder cancer clinical trials; (3) an improved understanding of current practice patterns regarding the use of perioperative chemotherapy in an effort to standardize care; (4) creation of a comprehensive handbook to assist researchers with developing bladder cancer databases; and (5) identification of response to therapy of high-grade non muscle invasive disease through a collaborative exchange of expertise and resources.

Detailed biopsy pathologic features as predictive factors for initial reclassification in prostate cancer patients eligible for active surveillance - Corrected Proof

2012-02-02

Abstract: Objective: To evaluate the impact of detailed biopsy characteristics such as positive cores location or multifocality on the risk of initial reclassification in prostate cancer (CaP) patients eligible for active surveillance (AS). Materials and methods: We reviewed data from 300 consecutive men eligible for AS (PSA ≤ 10 ng/ml, clinical stage T1c, Gleason score ≤6, <3 positive cores, extent of cancer in any core < 50%) who have undergone a radical prostatectomy (RP). Reclassification was defined as upstaged disease and/or upgraded disease in RP specimens. Results: Biopsy features showed 36% of CaP involving 2 cores and a mean total tumor length of 2.63 mm. The 2 most frequently positive sites were base and apex. Mean total tumor length was significantly associated with upgraded disease (P = 0.025). In a multivariate model taking into account PSA, PSAD, number of positive cores and total tumor length, a total tumor length > 5 mm were independently predictor for a upgraded disease (OR 1.93, P = 0.046). The number, the multifocality and the bilaterality of positive cores were not associated with reclassification. Upgraded disease was significantly less reported in case of positivity at midline zone compared with positivity at base, apex, or transition zone (P = 0.013). Conclusions: Detailed biopsy data provide additional information on the initial risk of reclassification in AS patients. Patients having a total tumor length < 5 mm and positive cores at midline zone are more likely to have favorable pathologic characteristics at diagnosis. These variables can be used for selection and monitoring improvement in AS programs.

Ureterorenoscopic biopsy and urinary cytology according to the 2004 WHO classification underestimate tumor grading in upper urinary tract urothelial carcinoma - Corrected Proof

2012-02-02

Abstract: Objectives: To determine accuracy of upper tract cytology and ureteroscopic biopsy according to the 2004 World Health Organization (WHO) classification in predicting the correct tumor grade in patients with urothelial cancer of the upper urinary tract (UUT-UC). Methods: Pathology reports of 77 nephroureterectomy specimens were retrospectively analyzed for tumor grade and compared with preoperatively gained cytology and ureteroscopic biopsy results. For analysis, the 2004 WHO classification was used. Results: Overall sensitivity of cytology and biopsy in diagnosis of UUT-UC was 64% and 74%, respectively. Accuracy of cytology and biopsy in predicting high grade cancer was 53% and 58%, respectively. Combination of cytology and biopsy could improve sensitivity (84%) and accuracy (68%), but even for this combination, 15% of high grade tumors were misinterpreted as low grade cancer. Conclusion: Our results show only limited accuracy for preoperative cytology and ureterorenoscopically performed biopsies in the prediction of the correct tumor grading of an UUT-UC. Therefore, we suggest the use of additional diagnostic procedures before the decision for definitive surgical treatment in patients with UUT-UC is made.

Fibroblast growth factor receptor-3 in urothelial tumorigenesis☆ - Corrected Proof

Gopa Iyer, Matthew I. Milowsky — 2012-01-30

Abstract: Fibroblast growth factor receptor-3 (FGFR3) is a receptor tyrosine kinase implicated in the tumorigenesis of multiple malignancies, including bladder and other urothelial cancers, multiple myeloma, and cervical cancer. In urothelial carcinoma (UC), constitutive receptor activation occurs most commonly through substitution of a wild-type residue with cysteine in the extracellular domain of FGFR3, thereby resulting in dimerization (through disulfide bridge formation) and subsequent stimulation of tyrosine kinase activity. Activating mutations of FGFR3 have been observed in up to 70% of non-muscle-invasive bladder tumors, while overexpression of a wild-type receptor, found in approximately 40% of tumors, has been correlated with more invasive disease. The identification of FGFR3 mutations in UC has sparked substantial interest in the therapeutic exploitation of these aberrations, and in vitro studies have provided evidence that such alterations may represent driver oncogenic lesions. In this review, we discuss the biologic and prognostic impact of FGFR3 mutations in UC as well as FGFR3 as a potential target for novel therapeutics.

Bacteriuria and antibiotic resistance in catheter urine specimens following radical prostatectomy1 - Corrected Proof

2012-01-30

Abstract: Objective: There are increasing reports of infectious complications following prostate biopsy due to fluoroquinolone resistance. To determine infectious complications at catheter removal following radical prostatectomy (RP), another setting in daily urological practice where fluoroquinolone prophylaxis is frequently used. Materials and methods: We prospectively examined urine culture results collected from 334 RP patients immediately prior to catheter removal. Patients received prophylactic antibiotics 1 day before, the day of, and for 5 days after catheter removal. Culture results were reviewed for bacterial species and antimicrobial susceptibilities. Patients with positive urine cultures resistant to the prophylactic antibiotic were switched to culture-specific antibiotic therapy and underwent follow-up culture. The frequency of urinary tract infection (UTI), complications, additional antibiotic therapy, and repeat urine cultures was determined within 60 days. Results: Of the 334 patients identified, 203 (61%) had cultures with no bacterial growth, and 48 (14%) had colony counts of <1,000 bacteria or Candida albicans and received no further antibiotics. The remaining 83 (25%) had positive culture results, of which 7% were resistant to ciprofloxacin. Twenty-four bacterial species were identified, with Pseudomonas aeruginosa (5%) Escherichia coli (4%), and Staphylococcus epidermidis (3%) being the most frequent. Only two (0.6%) men developed clinical symptoms consistent with UTI (i.e., suprapubic pain, fever) prior to catheter removal, and no serious complications occurred. Conclusions: A substantial proportion of RP patients have positive urine cultures at the time of catheter removal, despite the administration of prophylactic fluoroquinolone antibiotics. Potentially virulent organisms are commonly cultured, and ciprofloxacin resistance is frequent. However, outcomes are favorable when culture-specific oral antibiotic therapy is initiated.

Patients and partners lack knowledge of androgen deprivation therapy side effects - Corrected Proof

2012-01-30

Abstract: Objective: Androgen deprivation therapy (ADT) is the primary treatment for advanced prostate cancer (CaP). There is growing evidence that ADT negatively affects men's psychosocial well-being (e.g., causing sexual dysfunction, bodily feminization) and physical health (e.g., increasing the risk of osteoporosis and metabolic syndrome). Although strategies for managing the majority of side effects exist, it is not clear that patients are benefiting from this knowledge. Methods: Seventy-nine newly prescribed ADT patients and 54 of their partners were given a checklist of various common and uncommon ADT side effects. They were asked to indicate the drug side effects that they had heard of or anticipated. Results: Both patients and their partners were poorly informed about the side effects of luteinizing hormone-releasing hormone (LHRH) agonists used for ADT. More than 70% did not know that anemia, memory problems, loss of body hair, and depression can occur following treatment. Over 50% were unaware of significant potential side effects such as reduced muscle mass, osteoporosis, increased fracture risk, weight gain, genital shrinkage, and gynecomastia. Concurrently, more than 20% mistakenly anticipated dizziness and itching. Conclusion: The lack of awareness of ADT side effects may partially explain why ADT currently results in significant decreases in the quality of life of patients and their partners. Patients uninformed about side effects do not engage in behaviors to prevent or reduce the risk of adverse effects. Improved efforts to educate patients about treatment side effects and coping strategies may result in improved psychosocial and physical health for CaP patients undergoing ADT.

Capsular invasion in renal cell carcinoma: A meta-analysis - Corrected Proof

Turun Song, Yuan Yin, Banghua Liao, Shuo Zheng, Qiang Wei — 2012-01-30

Abstract: Objectives: Capsular invasion is frequently detected in localized renal cell carcinoma (RCCs) samples. Whether patients with localized RCCs and capsular invasion will suffer poorer clinical outcome than those without this pathologic finding is still at issue. Materials and methods: We performed a systematic literature research of Central, Medline, Embase, and Chinese database CNKI and VIP. Cohort studies comparing the prognosis in patients with localized RCCs and with or without capsular invasion were included. Incidence of capsular invasion in different Fuhrman grade, primary TNM stage, and clinical outcome were analyzed. Results: Six cohort studies with 2,295 eligible patients were identified. Capsular invasion was presented in 500 specimens (21.79%). Lower grade (Fuhrman I/II vs. Fuhrman III/IV) and stage (pT1 vs. pT2) diseases were associated with lower incidence of capsular invasion, with OR = 0.56, 95% CI[0.37–0.85] and OR = 0.35, 95% CI[0.25–0.49], respectively. Our pooled analysis showed patients with capsular invasive had 1.80 times the risk of tumor recurrence than patients without these findings (HR = 1.8, 95% CI [1.21, 2.68]), and patients with localized RCCs and capsular invasion were detected at 4.93 times risk in developing cancer related death than those without its presence during follow up (HR = 4.93, 95% CI [2.14, 11.35]). Conclusion: Patients with localized RCCs and capsular invasion are of poorer prognosis than those without this finding. Capsular invasion may serve as an additional factor in stratifying patient with localized RCCs.

Risk of renal cell carcinoma and polymorphism in phase I xenobiotic metabolizing CYP1A1 and CYP2D6 enzymes - Corrected Proof

2012-01-27

Abstract: The progressive increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the opinion that certain carcinogens present in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence and progression of this disease in developing countries like India. The polymorphism of the enzymes involved in metabolism of such environmental factors may, therefore, confer variable propensity to RCC. The possible association between RCC and a polymorphism of the CYP1A1 and CYP2D6 genes specific to the Indian population was examined using peripheral blood DNA from 196 RCC cases and 250 population controls with detailed data of clinicopathologic characteristics for the disease. The CYP1A1 (val) “variant” genotype, which contains at least 1 copy of the CYP1A1 variant alleles, was found to be associated with a 2.03-fold [GG ver. AA/AG, unadjusted OR = 2.03; 95%CI = 1.233–3.342; P = 0.005] increase in the risk of RCC. There was also a significant association (ptrend = 0.034) between higher frequency of RCC subjects containing at least of copy of the CYP1A1 (val) “variant” genotype with III or IV Fuhrman's grade. Whereas, the CYP2D6 polymorphism did not show any association with RCC risk [TT ver. CT/CC, unadjusted OR = 95%CI = 1.233–3.342; P = 0.005]. There was a significant association (ptrend = 0.001) between the poor metabolizer CYP2D6 (TT) and progression towards higher pathological stage of RCC. Our data demonstrate for the first time a significant association between pharmacogenetic polymorphisms of CYP1A1 and risk of RCC development in the Indian population. The findings suggest that inter-individual variation in the phase I metabolic enzymes involved in the fictionalization and detoxification of specific xenobiotics is an important susceptibility factor for development and progression of RCC in Indians.

Pre-existing type-2 diabetes is not an adverse prognostic factor in patients with renal cell carcinoma: A single-center retrospective study - Corrected Proof

2012-01-27

Abstract: Objectives: Type-2 diabetes mellitus (DM) is a metabolic disease affecting several million people all over the world. The correlation between DM and malignancies is well established due to the findings of several large population-based studies. However, for endometrial, breast, colorectal, and liver cancers it has also been reported that DM could exert a negative impact on prognosis, causing a significant reduction in cancer-specific survival. A significant correlation with DM has also been demonstrated in renal cell carcinoma (RCC), but the possible prognostic role of DM in this setting has been poorly investigated and remains controversial. This study provides a retrospective analysis of a single-center surgical series with the aim of assessing the features and prognosis of RCC in DM patients. Materials and methods: Since 1987 a prospectively compiled database at our institute has collected the data of 1,761 patients who underwent surgery for RCC. All the patients are followed in a specially dedicated out-patient ambulatory. For this study, patients who were taking insulin or oral anti-hyperglycemic drugs before surgery for RCC were considered as DM cases. Their clinical and pathologic features were compared with those of patients without DM. Then, limiting the analysis to non-metastatic patients, the Kaplan-Meier method was used to calculate survival functions and univariable and multivariable Cox regression models addressed time to RCC-related and non RCC-related mortality. Results: The data of 1,604 patients without DM and 157 with DM (prevalence 8.9%) have been analyzed; the latter were more frequently males, older, and with higher co-morbidity and with more asymptomatic, smaller, and low stage neoplasms, though with a higher grading. After a median follow-up time of 53.4 months (IQR 20–97 months), the factors that influenced RCC-related mortality were the presence of symptoms at diagnosis, tumor size, TMN staging, and grading, while those that influenced non-RCC-related mortality were age, gender, and co-morbidities, whereas the presence of DM showed no influence at all. Moreover, in patients without and with DM, progression rate (19.8% vs. 15.1%, P = 0.195) and RCC-related mortality rate (9.6% vs. 5.3%, P = 0.102) were also statistically equivalent. Conclusion: In our experience, the prevalence of DM in RCC patients is close to 10%. Such a condition does not determine any significant influence on prognosis of RCC.

Patterns of autophagy in urothelial cell carcinomas—the significance of “stone-like” structures (SLS) in transurethral resection biopsies - Corrected Proof

2012-01-27

Abstract: 0bjectives: To investigate the microtubule-associated protein LC3A, presumed to reflect autophagic activity, in urothelial cell carcinomas (UCC) for its relevance with muscle invasion in transurethral resection (TUR) biopsies. The LC3A antibody is specific for identifying the autophagy-related protein Atg8 and, hence, autophagy—a self-degradation mechanism by which cells recycle their own cytoplasmic constituents, providing with additional energy the rapidly proliferating cells. Methods: The study comprised 210 TUR specimens of UCC of the urinary bladder: 70 low-grade non-muscle-invasive (NMI, group A), 70 high-grade NMI (group B), and 70 high-grade muscle invasive tumors (group C). These, together with 40 controls, were stained for Atg8/LC3 using an automated immunohistochemical technique. Results: The LC3A was detected as diffuse cytoplasmic staining, and as dense, spheroidal, “stone-like” structures (SLS) of variable size (1.2–12.0 μm in diameter), typically enclosed within cytoplasmic vacuoles. The LC3A reactivity, whether expressed in the form of SLS or as diffuse cytoplasmic staining, was higher in high-grade UCC than in low-grade disease and, more importantly, it was associated with muscle invasion. The median number of SLS per optical field, per section was 17.0, 19.0, and 37.0 for groups A, B, and C, respectively (A, B vs. C P < 178> 0.0001; A vs. B P = 0.27). The median SLS diameter was 4.9, 5.3, and 9.3 μm for groups A, B, and C respectively (A, B, vs. C P < 0.0001; A vs. B P = 0.03). Conclusion: It appears that the LC3A protein is closely connected with muscle invasion, but whether this finding is of clinical value in TUR specimens lacking muscularis propria remains to be proven.

The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor - Corrected Proof

2012-01-24

Abstract: Objective: Emerging evidences implicate long noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose of the current study is to investigate the role of new lncRNA, named PlncRNA-1, in prostate cancer (CaP) pathogenesis. Materials and methods: In this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues, 14 pairs CaP tissues and BPH tissues, 4 CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E. After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR. Results: We showed that expression PlncRNA-1, was significantly higher in CaP cells relative to normal prostate epithelial cells, as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI. Mechanistically, PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines. Conclusions: Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target.

Adjuvant and neoadjuvant therapy for renal cell carcinoma: A survey of the Society of Urologic Oncology - Corrected Proof

Conrad M. Tobert, Robert G. Uzzo, Christopher G. Wood, Brian R. Lane — 2012-01-24

Abstract: Objective: Several systemic agents have been approved for patients with advanced renal cell carcinoma (RCC) and others are in various stages of development. We surveyed members of the Society of Urologic Oncology (SUO) regarding the importance of adjuvant and neoadjuvant systemic therapy for RCC and their participation in such trials. Materials and methods: A survey was sent in October 2010 to 564 U.S. and Canadian members of the SUO and the SUO-Clinical Trials Committee with a valid e-mail address. A total of 136 urologic cancer specialists from a mixture of practice patterns responded to the questionnaire (24% participation rate). Results: At the time of the study, 75% participated in adjuvant or neoadjuvant treatment protocols, including 75% with adjuvant and 16% with neoadjuvant protocols. There was universal support for continued investigation of agents for adjuvant use in RCC with locoregional metastasis (100%) and nearly universal support for investigation of agents in patients with “high risk” (99%) and “intermediate risk” (91%) localized RCC after nephrectomy. The vast majority of respondents also supported investigation of neoadjuvant therapies in patients with advanced RCC (98%) or locally-advanced RCC (98%), with 70% also supporting neoadjuvant trials in patients with localized RCC. Importantly, 98% of respondents indicated interest in participating in future adjuvant and neoadjuvant trials. Conclusion: Urologic cancer specialists surveyed in late 2010 demonstrated nearly universal support for trials to investigate the role of neoadjuvant and adjuvant therapies for RCC of all stages. With appropriate patient selection and outcome assessment, this widespread support indicates great potential for future clinical trials which will require the participation of urologic surgeons.

Positive surgical margins at radical prostatectomy: Much ado about nothing? - Corrected Proof

Matthew J. Resnick, Michael S. Cookson — 2012-01-13

“Medicine is a science of uncertainty and an art of probability.” -William Osler. The finding of positive surgical margins (PSM) following radical prostatectomy (RP) continues to induce angst amongst the surgeon and the patient alike. Unquestionably, the chance of cancer recurrence is greater in the patient with PSM compared with the patient with negative surgical margins. However, predicting the probability of cancer recurrence in any individual patient based solely on margin status remains inexact. Additionally, optimal management of patients with PSM remains controversial with no uniform consensus despite the publication of 3 well-performed randomized trials evaluating the benefit of immediate postoperative radiation in patients with adverse pathologic features . This discussion will review the limitations of a PSM as a marker of surgical effectiveness, the implications of PSM following RP, risk-stratification within the subgroup of patients with PSM, and implications for treatment.

Radical prostatectomy: Positive surgical margins matter - Corrected Proof

Joshua J. Meeks, James A. Eastham — 2012-01-13

Abstract: Objective: A positive surgical margin (PSM) in the radical prostatectomy (RP) specimen is associated with biochemical recurrence (BCR) and the need for adjuvant radiation therapy, and is a surrogate for surgical quality. We review the available data describing the identification, anatomy, and management of PSM after RP. Methods: A PubMed search (using English language as a filter) was performed to identify factors affecting PSMs and their management. Results: PSMs are associated with an increased likelihood of BCR after RP. The most common location for a PSM is the apex, followed by the posterolateral edge of the prostate. The risk of recurrence in a patient with a PSM is associated with the location, length, and Gleason score of the PSM. The management of a patient with a PSM remains controversial, with some recommending adjuvant radiation therapy for all PSMs and others suggesting only salvage radiation therapy for men who experience BCR. Conclusions: PSMs are associated with an increased likelihood of BCR and often result in initiation of adjuvant treatment. Therefore, the goal of surgery should be to minimize the likelihood of a PSM.

Natural history of untreated renal cell carcinoma with venous tumor thrombus - Corrected Proof

Adam C. Reese, Jared M. Whitson, Maxwell V. Meng — 2012-01-12

Abstract: Objectives: The natural history of untreated renal cell carcinoma (RCC) with venous tumor thrombus (VTT) is poorly characterized. We aimed to describe the natural history of this disease, and to identify prognostic factors associated with disease-specific survival. Materials and methods: We identified patients in the Surveillance, Epidemiology, and End Results (SEER) database with untreated renal cell carcinoma and venous tumor thrombi. Disease-specific median and 1-year survival rates were determined, and disease-free survival curves were plotted using the Kaplan-Meier method. Multivariable Cox regression analyses were performed to identify factors associated with disease-specific and overall survival in this patient group. Results: Of 2,265 patients with RCC and VTT, 390 (17%) underwent no treatment; 278 (71%) patients died during follow-up; of these, 243 deaths (87%) were due to RCC. Median and 1-year disease-specific survival for this group was 5 months and 29%, respectively. On multivariable analysis, the extent of tumor thrombus (HR 1.7 for T3c vs. T3b, 95% CI 1.0–2.7) and the presence of metastases (HR 3.1 for M+ vs. M0, 95% CI 1.7–5.5) were most strongly associated with disease-specific mortality. Conclusions: Prognosis is poor for the majority of untreated patients with RCC and VTT. Supradiaphragmatic thrombi and distant metastases are adverse prognostic factors in this patient group. This information is important when counseling patients as to the risk and benefits of surgical vs. nonoperative management of RCC and VTT.

A novel role of Id-1 in regulation of epithelial-to-mesenchymal transition in bladder cancer - Corrected Proof

2012-01-09

Abstract: Background and objective: Inhibitor of differentiation or DNA binding -1 (Id-1) has been shown to be increased in several types of advanced cancer, and to be associated with aggressive and metastatic abilities of cancer cells. Recently, more and more evidence indicates that epithelial-to-mesenchymal transition (EMT) is an important mechanism taking place during tumor invasion and metastasis, but the molecular pathways underlying EMT have not been clearly established. This study was to investigate the expression of Id-1 in bladder cancer and its association with EMT. Materials and methods: A total of 169 tissues, consisting of 147 primary bladder cancers and 22 adjacent normal tissues were included in this study. Id-1, E-cadherin, and β-catenin were examined immunohistochemically in paraffin sections. The pBabe-Id-1 expression retroviral vector and retroviral vectors containing an Id-1-specific small interfering RNA oligonucleotides (si-Id-1) were transfected into 2 bladder cancer cell lines respectively. Then, we used Western blotting and immunofluorescent staining to detect the cellular expression of epithelial markers and mesenchymal markers. The invasion and migration ability of bladder cancer cells were identified by type I collagen invasion assay and wound closure assay. Results: We demonstrated that increased Id-1 expression was associated with advanced tumor stage and grade. In addition, the increased Id-1 expression in bladder tumors was also correlated with decreased membranous E-cadherin and β-catenin expression. In vitro, studies showed that inactivation of the Id-1 gene conferred morphologic transition of bladder cancer cells from a fibroblastic to epithelial appearance, and overexpression of Id-1 could lead to acquisition of a fibroblastic spindle cell phenotype accompanied by loss of cell-to-cell contacts. By Western blotting and immunofluorescent staining, we showed that the expression level of Id-1 was correlated with the expression of mesenchymal markers but was inversely correlated with the expression of epithelial markers. Moreover, results of collagen invasion and wound closure assays showed ectopic Id-1 expression led to increased ability of invasion and migration. Conclusions: Our results suggest that Id-1 may play roles in tumor progression and EMT activation in bladder cancer.

Chronic hypoxia induces androgen-independent and invasive behavior in LNCaP human prostate cancer cells - Corrected Proof

Mutsushi Yamasaki, Takeo Nomura, Fuminori Sato, Hiromitsu Mimata — 2012-01-09

Abstract: Purpose: Tumor hypoxia is a common feature of any cancer, including prostate cancer (CaP), and associated with tumor cell aggressiveness. Although some reports are available on acute hypoxia-response in CaP cells aggressiveness, little is known about chronic hypoxia-response. We investigated the effects of chronic hypoxia on human CaP cells. Materials and methods: The human androgen-dependent CaP cell line LNCaP was cultured under normoxia (21% O2), acute hypoxia (1% O2), or chronic hypoxia (1% O2 for over 6 months). The cell growth, cell cycle and cell behavior of these cells were analyzed by cell count, flow cytometric analysis and in vitro cell migration and invasion assay, respectively. The expression of matrix metalloproteinases and intracellular signaling pathways were tested by real time reverse transcriptase-polymerase chain reaction and Western blotting. Results: Chronic hypoxia-conditioned LNCaP cells grew in an androgen-independent manner with acceleration of G1 to S phase cell cycle progression. Chronic hypoxia, but not acute hypoxia, accelerated cell migration and invasion. The expressions of matrix metalloproteinase-7, -9, -14, and -15 were significantly up-regulated in LNCaP cells under chronic hypoxia, but not under acute hypoxia. In addition, PI3K/Akt, JAK/STAT, and HIF-1 pathways were activated in chronic hypoxia-conditioned LNCaP cells. Conclusions: These results suggested that chronic hypoxia plays an important role in enhancement of malignant potential during androgen-independent CaP progression.

Open vs. robotic-assisted radical prostatectomy: A single surgeon and pathologist comparison of pathologic and oncologic outcomes - Corrected Proof

Timothy A. Masterson, Liang Cheng, Ronald S. Boris, Michael O. Koch — 2012-01-06

Abstract: Objective: To compare the impact surgical technique has on clinicopathologic and oncologic outcomes among patients undergoing radical prostatectomy for clinically localized prostate cancer. Materials and methods: Utilizing the experience of a single surgeon and pathologist, a retrospective review of 1,041 patients undergoing open (RRP) and robotic-assisted (RALP) radical prostatectomy between 1999 and 2010 with pathologic evaluation using whole-mount sectioning techniques and tumor mapping was performed from our prospective database. Differences in the incidence, location, and linear length of positive surgical margins were compared. Additionally, rates of biochemical relapse-free survival according to technique were assessed. Results: A total of 357 RRP and 669 RALP patients were evaluated. The overall incidence of surgical margin positivity when stratified by stage of disease and location of positive margins was nearly identical between groups for organ confined disease. The apex and posterior surfaces represented the 2 most common locations for positive margins. RALP had notably fewer positive margins in pathologic T3 disease and a statistically shorter linear length of margin positivity among all patients. Short and intermediate-term biochemical-free survival rates were identical between groups. Conclusions: RALP is associated with operative oncologic control rates that compare very favorably to RRP. The data suggest that in the hands of an experienced surgeon, RALP has oncologic outcomes that are at least as good if not better than RRP.

Smaller prostate gland size and older age predict Gleason score upgrading - Corrected Proof

2011-12-30

Abstract: Objectives: Gleason score is important for prostate cancer (CaP) risk stratification and prognostication but has a significant rate of upgrading. We examined the effect of prostate size and age on upgrading of Gleason 6 CaP. Materials and methods: A retrospective review was performed of patients with Gleason 6 CaP who underwent radical prostatectomy from 2001 through 2010. Preoperative clinical and pathologic variables were assessed to determine association with risk of upgrading at prostatectomy. Results: A total of 1,836 patients were identified with Gleason 6 on prostate biopsy. Upgrading was observed in 543 (29.6%) patients with a final Gleason score of 3+4 in 463 (25.2%), 4+3 in 49 (2.7%), and 8–10 in 31 (1.7%). On univariate logistic regression, age, prostate weight, and PSA were significant predictors of Gleason score upgrading and remained significant on multiple logistic regression. Prostate weight was inversely related to risk of upgrading. To further explore this effect, we performed multiple logistic regression to examine risk of Gleason 6, 7, or 8–10 disease in 2,493 patients with Gleason 6–10 at prostatectomy. After controlling for age and PSA, there was a progressively increased risk of Gleason 6, 7, and 8–10 disease with decreasing prostate weight. Conclusions: Older age, higher PSA, and smaller prostate gland size are associated with increased risk of Gleason score upgrading. The inverse relationship of prostate weight to risk of Gleason upgrading may be related to increased high-grade disease in smaller glands.

Bladder cancer: A window of opportunity to understand carcinogenesis - Corrected Proof

Kevin R. Loughlin — 2011-12-26

Abstract: Bladder cancer provides a unique opportunity to apply our knowledge of the molecular biology of the malignancy to its clinical behavior and prognosis. Urologists should apply the increasing fund of basic science knowledge to the clinical management of bladder cancer.

Measurement of PSA density by 3 imaging modalities and its correlation with the PSA density of radical prostatectomy specimen - Corrected Proof

2011-12-26

Abstract: Objective: To evaluate the difference between the PSA density (PSAD) calculated with 3 imaging modalities and the PSAD of the radical prostatectomy specimen. Materials and methods: The PSAD of 60 men with clinically localized prostate cancer was calculated with transabdominal ultrasound (TAUS), transrectal ultrasound (TRUS), and computed tomography (CT) before radical retropubic prostatectomy, and was compared with the PSAD of the surgical specimen using the paired t-test. The relationship of the real prostate volume and the difference between the PSAD calculated with the 3 imaging modalities and that of the PSAD of the specimen was analyzed using Pearson's correlation coefficient. Finally, the sensitivity of PSAD calculated with the examined imaging modalities and the specimen was also studied. Results: The mean difference between the PSAD calculated by each one of the 3 imaging modalities and the PSAD of the specimen was −0.01 ng/ml/cm3 (P = 0.28) for TAUS, 0.01 ng/ml/cm3 (P = 0.37) for TRUS, and −0.03 ng/ml/cm3 (P = 0.001) for CT. This difference has not been shown to depend on the real prostate volume according to Pearson's correlation coefficient, which was 0.056 (P = 0.673) for TAUS, −0.014 (P = 0.917) for TRUS, and 0.184 (P = 0.159) for CT. The sensitivity of PSAD calculated with TAUS, TRUS, and CT was 58.3%, 65%, and 45%, respectively, while that of the specimen was 70%. Conclusions: Although PSAD showed a moderate sensitivity, TRUS and TAUS are the imaging modalities that calculate it closer to the real PSAD of the specimen.

High expression of polo-like kinase 1 is associated with the metastasis and recurrence in urothelial carcinoma of bladder - Corrected Proof

Zhe Zhang, Guojun Zhang, Chuize Kong — 2011-12-22

Abstract: Objectives: Polo-like kinase 1 (Plk1) has been widely pursued as an oncology target because it is overexpressed in several human tumor types. To investigate whether Plk1 plays a general role in bladder urothelial carcinoma, we examined the expression of Plk1 protein in bladder urothelial carcinoma and cell lines, and analyzed the relationship among Plk1 protein expression, metastasis, and recurrence of urinary bladder urothelial carcinoma. Methods: Immunohistochemistry was used to detect the expression of Plk1 in 120 bladder urothelial carcinoma. Moreover, the expression of Plk1 was analyzed by Western blot in 60 bladder urothelial carcinoma and 21 normal epithelial tissues. MTT assay and flow cytometry and transwell assay were used to examine the proliferative and invasive ability of bladder cancer cells with the treatment of scytonemin (the inhibitor of Plk1). Statistical analysis was used to discuss the association between Plk1 expression and clinicopathologic parameters, tumor metastasis and recurrence, and the proliferative and invasive ability and cell cycle process of the bladder cancer cells. Results: There was a significantly higher Plk1expressions in bladder urothelial carcinoma and highly invasive bladder T24 cells than those in bladder normal tissues and the superficial bladder BIU-87 cells. Plk1 expression was positively correlated with histologic grade, pT stage, recurrence, and metastasis. With the increasing concentration of scytonemin, we found that not only the cell proliferation and invasion activity decreased significantly, but also the cell cycle was blocked at G2/M stage. Conclusion: Plk1 expression status was closely correlated with important histopathologic characteristics (grades and stages) and the recurrence and metastasis of bladder urothelial carcinomas. Furthermore, Plk1 played an important function on the bladder cancer cells' proliferation by regulating the cancer cell cycle from G1/S to G2/M and probably promoted the invasion and metastasis of bladder cancer.

Polymorphisms of TP53 are markers of bladder cancer vulnerability and prognosis - Corrected Proof

2011-12-19

Abstract: Objectives: We have reported previously that the TP53 codon72 polymorphism (rs1042522) is associated with the incidence and invasiveness of bladder cancer in a Han Chinese population. Using an enlarged sample, we investigated the role of rs1042522 and of tagSNPs that were predicted to be in linkage disequilibrium with codon72 in relation to the incidence, invasiveness, and prognosis of bladder cancer. Methods and materials: A sample of 201 patients and 311 controls without cancer were genotyped for 5 tagSNPs using tetra-primer ARMS and/or an allele-specific PCR technique. Results: The genotyped data were analyzed using Haploview 4.2, and a 10,000-permutation test showed that the rs9895829G allele (P = 0.003) and the rs1788227C allele (P = 0.027) were both associated with the incidence of bladder cancer. With respect to haplotype associations, after the data were adjusted for age, the haplotypes GTT (P = 0.001) and GGTC (P < 0.001) were correlated with a low incidence of bladder cancer. In contrast, none of the TP53 haplotypes were associated significantly with high tumor grade or muscle invasiveness. On the basis of Cox regression analysis, haplotype CGCC and invasiveness were associated with cancer-related death. Structural equation modeling showed that haplotypes GGCC and CGCC played opposing roles with respect to bladder cancer-related death; haplotype GGCC was a protective factor, whereas haplotype CGCC was a risk factor. Conclusions: The TP53 codon72 polymorphism appears to play a crucial role in determining the association between TP53 haplotype and the incidence and prognosis of bladder cancer. Further functional assays to confirm whether these TP53 haplotypic variants interact with the proteins N-Myc and NDRG is necessary.

Stress-activated kinase pathway alteration is a frequent event in bladder cancer - Corrected Proof

Kristen B. Otto, Sujeet S. Acharya, Victoria L. Robinson — 2011-12-12

Abstract: Objectives: The stress-activated MAP kinases (SAPK) signaling pathways play a critical role in the cellular response to toxins and physical stress, mediate inflammation, and modulate carcinogenesis and tumor metastasis. The stress-activated MAP kinases (MAPK) c-Jun N-terminal kinase (JNK) and p38 are activated upon phosphorylation by a widely expressed and conserved family of upstream MAP kinase kinases (MAP2K). Signaling mediated by p38 and JNK has well-established importance in cancer, yet the contribution of this pathway in urothelial bladder cancer is not understood. This study evaluated stress-activated MAP kinase pathway expression in cell lines derived from human urothelial carcinomas. Materials and methods: Total protein lysates from a panel of human urothelial bladder cancer cell lines (RT4, T24, UMUC-3, J82, 5637, 253J, and 253J-BV) were analyzed by immunoblotting for the JNK and p38 MAPKs, as well as MKK3, MKK4, MKK6, and MKK7. Quantitative real time PCR was utilized to determine mRNA expression levels of the MAP2Ks. Stress stimuli (sorbitol, hydrogen peroxide, and UV irradiation) were used to active p38, which was measured by phospho-antibody. Results: Although protein levels were variable, all cell lines expressed p38 and JNK. On the other hand, with the exception of the well-differentiated cell line RT4, each cell line had a reduction or absence of expression of one or more MAP2K. 253J and 253J-BV exhibited no expression of MKK6, even when an excess of protein was queried. mRNA levels indicated that both transcriptional and post-transcriptional mechanisms are involved in the regulation of MAP2Ks. Decreased MAP2K expression correlated with decreased ability to activate p38 in response to stress stimuli. Conclusions: Aberrant MAP2K protein expression indicates that altered cellular signal transduction mediated via JNK and p38 may be common in bladder cancer. Down-regulation of MAP2Ks likely occurs at both the transcriptional and post-transcriptional levels. Consistent with the known function of p38 and JNK in apoptosis, defects in normal pathway function caused by decreased expression of upstream MAP2Ks may provide a survival advantage to bladder cancer cells. Further investigations should focus on identifying a functional role for these pathways in bladder cancer development.

The surgical management and prognosis of renal cell cancer with IVC tumor thrombus: 15-Years of experience using a multi-specialty approach at a single UK referral center - Corrected Proof

2011-12-12

Abstract: Objectives: Surgical management of renal cell carcinoma (RCC) invading the inferior vena cava (IVC) remains a technical challenge. However, radical surgery is the only potentially curative treatment. We set out to review our experience of using a multi-specialty approach to these patients over the last 15 years. Patients and methods: Fifty patients with RCC and IVC invasion underwent surgery at our institution (mean age: 59 years). Tumor thrombus was infrahepatic/levels I and II: n = 24, intrahepatic/level III: N = 14, or suprahepatic/level IV: n = 12. Infra- and intrahepatic caval tumors were resected using an abdominal approach and liver transplant techniques without cardiopulmonary bypass (CPB). CPB was used only with level IV thrombus. Results: There were no intraoperative deaths. Median operating time was 6 hours and blood loss 3.5 liters (l). Staging was T3b: n = 34, T3c: n = 10 and T4: n = 6. Median time spent in HDU and hospital were 2 and 12.5 days, respectively. Perioperative mortality was 4%. Metastatic disease (P < 0.001) and level IV thrombus (P < 0.05) were significant negative prognostic factors. Forty of the 50 patients did not have metastasis. With mean follow-up of 38 months, the non-metastatic group had 2-year estimated Kaplan-Meier survival of 82.0% falling to 62.4% at 5 years. Conversely, in the metastatic group, estimated 2-year survival was 26.6% falling to 0% by 5 years. Conclusion: Surgical treatment of RCC involving the IVC is possible with acceptable morbidity and mortality. Long-term survival can be expected in over 60% of non-metastatic patients at 5 years. These cases benefit from a multidisciplinary surgical approach. Level III thrombus can be successfully managed without CPB.

In vivo and in vitro effects of RAD001 on bladder cancer - Corrected Proof

2011-12-12

Abstract: Objective: To evaluate the influence of Everolimus (RAD001) on chemically induced urothelial lesions in mice and its influence on in vitro human bladder cancer cell lines. Methods: ICR male mice were given N-butyl-N-(4-hydroxybutyl) nitrosamine in drinking water for a period of 12 weeks. Subsequently, RAD001 was administered via oral gavage, for 6 weeks. At the end of the experiment, all the animals were sacrificed and tumor development was determined by means of histopathologic evaluation; mammalian target of rapamycin (mTOR) expressivity was evaluated by immunohistochemistry. Three human bladder cancer cell lines (T24, HT1376, and 5637) were treated using a range of RAD001 concentrations. MTT assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry were used to assess cell proliferation, apoptosis index, and cell cycle analysis, respectively. Immunoblotting analysis of 3 cell line extracts using mTOR and Akt antibodies was performed in order to study the expression of Akt and mTOR proteins and their phosphorylated forms. Results: The incidence of urothelial lesions in animals treated with RAD001 was similar to those animals not treated. RAD001 did not block T24 and HT1376 cell proliferation or induce apoptosis. A reduction in cell proliferation rate and therefore G0/G1 phase arrest, as well as a statistically significant induction of apoptosis (P = 0.001), was only observed in the 5637 cell line. Conclusion: RAD001 seems not to have a significant effect on chemically induced murine bladder tumors. The effect of RAD001 on tumor proliferation and apoptosis was achieved only in superficial derived bladder cancer cell line, no effect was observed in invasive cell lines.

Association of genetic polymorphism of glutathione S-transferase (GSTM1, GSTT1, GSTP1) with bladder cancer susceptibility - Corrected Proof

Mohammad Reza Safarinejad, Saba Safarinejad, Nayyer Shafiei, Shiva Safarinejad — 2011-12-12

Abstract: The glutathione-S-transferases (GSTs) comprise a class of enzymes that detoxify carcinogenic compounds by conjugating glutathione to facilitate their removal. Polymorphisms in GSTM1, GSTT1, and GSTP1 genes have been related to risk for bladder cancer. Studies focusing on GSTs gene variants relationship with the risk of bladder cancer have produced conflicting and inconsistent results. We examine the association between genetic polymorphism of glutathione S-transferase P1, GSTM1, GSTT1 genes and development of bladder transitional cell carcinoma (TCC). The study population consisted of 166 histologically confirmed male bladder TCC cases and 332 healthy male controls. Genotyping was done using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and also investigated combined gene interactions. The GSTP1 Val/Val genotype was significantly associated with bladder cancer (OR = 4.32, 95% CI: 2.64–6.34), whereas the association observed for GSTM1 null (OR = 1.32, 95% CI: 0.82–2.62; P = 0.67) and GSTT1 null genotype (OR = 1.18, 95% CI: 0.79–1.67; P = 0.74) did not reach statistical significance. There was a significant multiple interaction between GSTM1, GSTT1, and GSTP1 genotypes in risk of bladder cancer (P for interaction = 0.02). The risk associated with the concurrent presence of GSTM1 positive and GSTP1 Ile/Val or Val/Val (OR = 3.71, 95% CI: 2.34–5.54) and GSTT1 positive and GSTP1 Ile/Val or Val/Val (OR = 2.66, 95% CI: 1.54–4.72) was statistically significant. Patients carrying GSTP1 Val/Val genotype were at increased risk for developing high-grade (OR = 7.68, 95% CI: 4.73–19.25) and muscle invasive (OR = 10.67, 95% CI: 6.34–21.75) bladder cancer. High risk for bladder TCC also was observed with respect to combined GSTT1 null/GSTP1 Ile/Val or Val/Val (OR = 4.76, 95% CI: 2.68–18.72) and GSTM1 null/GSTT1 null/GSTP1 Ile/Val or Val/Val (OR = 6.42, 95% CI: 4.76–14.72) genotype variant. This study suggests that the GSTP1 polymorphism and its combination with GSTM1, and GSTT1 may be associated with bladder cancer susceptibility in the Iranian population. Further confirmation in large population-based studies is needed.

The significant immunological characteristics of peripheral blood neutrophil-to-lymphocyte ratio and Fas ligand expression incidence in nephrectomized tumor in late recurrence from renal cell carcinoma - Corrected Proof

2011-12-09

Abstract: Objective: In order to characterize the significance of immune system function in patients with advanced renal cell carcinoma (RCC), we investigated the interactive relationships among the following parameters: metastatic characteristics, expression of Fas ligand (FasL) in nephrectomized specimens, immunological parameters, and patient's prognosis. Materials and methods: Thirty-five patients with advanced RCC were stratified into 3 groups according to the characteristics of metastasis timing, at first presentation (mFP), within 5 years of nephrectomy (early-recurrence), after 5 years (late-recurrence). Immunological parameters [hemoglobin, lymphocyte count, neutrophil/lymphocyte ratio (NLR), serum albumin, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and Charlson Comorbidity Index], FasL expression in RCC, and patient prognosis from occurrence of metastasis were compared among the groups. Thirty-five patients were also stratified into 2 groups according to FasL positivity and individual parameters. Patient's prognosis and the remaining immunological parameters were compared between groups. Results: The NLRs of the late-recurrence group were significantly lower than those of the mFP (P = 0.0004) and early-recurrence (P = 0.013) groups. The FasL mRNA positivity of the late-recurrence group was significantly lower than those of the mFP (P = 0.001) and early-recurrence (P = 0.0277) groups. The prognosis of the late-recurrence group was significantly better than that of the early-recurrence group (P = 0.0255). NLRs were significantly lower in the FasL-negative group than in the -positive group (P = 0.0182). The cause-specific survival rates of the ECOG PS 0 group were significantly higher than that of the ECOG PS > 0 group (P < 0.0001). Conclusions: Our results suggest the associations of the prognosis in advanced RCC with peripheral blood NLR and FasL expression in nephrectomized tumor. The characteristics of lower values of NLR and FasL expression positivity in late-recurrence compared with other metastatic timings suggest strong host immune activity, and may imply relatively long survival. On the other hand, elucidation of the patient's general condition obtained not only by chemical data but also by ECOG PS is crucial in the management of patients with advanced RCC.

The Personal Patient Profile-Prostate decision support for men with localized prostate cancer: A multi-center randomized trial - Corrected Proof

2011-12-09

Abstract: Objective: The purpose of this trial was to compare usual patient education plus the Internet-based Personal Patient Profile-Prostate, vs. usual education alone, on conflict associated with decision making, plus explore time-to-treatment, and treatment choice. Methods: A randomized, multi-center clinical trial was conducted with measures at baseline, 1-, and 6 months. Men with newly diagnosed localized prostate cancer (CaP) who sought consultation at urology, radiation oncology, or multi-disciplinary clinics in 4 geographically-distinct American cities were recruited. Intervention group participants used the Personal Patient Profile-Prostate, a decision support system comprised of customized text and video coaching regarding potential outcomes, influential factors, and communication with care providers. The primary outcome, patient-reported decisional conflict, was evaluated over time using generalized estimating equations to fit generalized linear models. Additional outcomes, time-to-treatment, treatment choice, and program acceptability/usefulness, were explored. Results: A total of 494 eligible men were randomized (266 intervention; 228 control). The intervention reduced adjusted decisional conflict over time compared with the control group, for the uncertainty score (estimate −3.61; (confidence interval, −7.01, 0.22), and values clarity (estimate −3.57; confidence interval (−5.85,−1.30). Borderline effect was seen for the total decisional conflict score (estimate −1.75; confidence interval (−3.61,0.11). Time-to-treatment was comparable between groups, while undecided men in the intervention group chose brachytherapy more often than in the control group. Acceptability and usefulness were highly rated. Conclusion: The Personal Patient Profile-Prostate is the first intervention to significantly reduce decisional conflict in a multi-center trial of American men with newly diagnosed localized CaP. Our findings support efficacy of P3P for addressing decision uncertainty and facilitating patient selection of a CaP treatment that is consistent with the patient values and preferences.

Consolidative surgery after targeted therapy for renal cell carcinoma - Corrected Proof

Anil A. Thomas, Steven C. Campbell — 2011-12-09

Abstract: Renal cell carcinoma is the most lethal of the common genitourinary neoplasms, with 30% to 40% of patients eventually dying from disease progression. Although the recent development of targeted therapies against kidney cancer has yielded substantially improved tumor response rates and progression-free survival, these agents are still not curative. The integration of systemic therapies with surgery still represents the best management for select patients with advanced disease. Specifically, consolidative surgery may play a vital role in the management of this challenging patient population. However, concerns remain regarding the potential for increased surgical morbidity complicating the integration of surgery after targeted therapy. Careful patient selection and specific precautions to increase surgical safety should be implemented.

Orthotopic sigmoid vs. ileal neobladders in Japanese patients: A comparative assessment of complications, functional outcomes, and quality of life - Corrected Proof

2011-12-08

Abstract: Objectives: To compare the clinical outcomes of sigmoid and ileal neobladders (NBs) created following radical cystectomy. Materials and methods: This study included 90 and 144 Japanese patients undergoing radical cystectomy and orthotopic NB reconstruction with a sigmoid and ileal segment, respectively. Postoperative clinical outcomes between the sigmoid and ileal NB groups (SNBG and INBG) were compared. Results: In this series, 110 early and 51 late complications occurred in 71 and 41 patients, respectively; however, there was no significant difference in the incidence of complications between SNBG and INBG. At 1 year postoperatively, there were no significant differences in the proportion of spontaneous voiders and the continence status between these 2 groups; however, despite the lack of significant differences in the maximal flow rate and voided volume, the post-void residual in SNBG was significantly smaller than that in INBG. Voiding functional outcomes at 5 years postoperatively were also obtained from 28 and 49 in SNBG and INBG, respectively. Although there were no significant changes in the functional outcomes in SNBG, the proportion of spontaneous voiders and post-void residual in INBG at 5 years postoperatively were significantly poorer than those at 1 year postoperatively. Furthermore, the postoperative health-related quality of life assessed by a Short-Form 36 survey did not show any significant differences in all 8 scores between these 2 groups. Conclusions: Both types of NB reconstruction resulted in comparatively satisfactory outcomes; however, the voiding function, particularly that on long-term follow-up, in SNBG appeared to be more favorable than that in INBG.

Alterations in the extracellular catabolism of nucleotides are involved in the antiproliferative effect of quercetin in human bladder cancer T24 cells - Corrected Proof

2011-12-06

Abstract: Bladder cancer is the most prevalent tumor in the genitourinary tract and the current treatments are not efficient to prevent recurrence and progression of tumor cases. Studies have revealed evidence of the involvement of the purinergic system in bladder tumorigenesis, particularly ecto-5′-NT/CD73, the enzyme responsible for AMP hydrolysis. Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a plant-derived flavonoid that has been shown to exert a broad range of pharmacologic properties, including potential anticancer activity. Here, we investigated the quercetin effect on the E-NTPDases and ecto-5′-nucleotidase/CD73, which catalyzes the introversion of the extracellular purine nucleotides in T24 human bladder cancer cells. The results showed that this flavonoid was able to increase ADP hydrolysis and inhibit the ecto-5′-nucleotidase/CD73 activity, with no effect on protein expression. The treatment with APCP (α,β-methyleneadenosine-5′-diphosphate), another ecto-5′-NT/CD73 inhibitor, led to a significant reduction in cell proliferation. In addition, we showed that AMP, which can be accumulating by enzyme inhibition, had an antiproliferative effect on T24 cells, which was enhanced when its hydrolysis was inhibited by APCP treatment. Otherwise, adenosine did not cause any significant effect on cell proliferation and the quercetin effects were not altered by the simultaneous presence of adenosine. Taken together, the results suggest that the antiproliferative effect of quercetin on tumor cells may occur, at least in part, via alterations in the extracellular catabolism of nucleotides, that could be by AMP accumulation, or could be due to blocked adenosine receptors by this flavonoid, supporting the potential use of quercetin in bladder cancer treatment.

Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells - Corrected Proof

2011-12-02

Abstract: Background: Tumor hypoxia is a common feature of prostate tumors associated with the stabilization of hypoxia-inducible-factor 1alpha (HIF-1α) and poor prognosis following radiation therapy. Lack of oxygen at the time of irradiation is associated with radioresistance, but recent reports suggest radioresponse is also modulated by the dynamic nature of tumor hypoxia.Objective: We proposed to evaluate the effect of post-irradiation hypoxic exposure on the radioresponse of 2 prostate cancer (CaP) cell lines (22Rv1, DU145) and to examine whether it correlates with modified cellular responses induced by hypoxia.Methods and results: Aerobic and hypoxic CaP cells exposed to hypoxia (24 h) after irradiation (4 Gy) gained a survival advantage compared with cells fully oxygenated after irradiation. This survival advantage was associated with induction of a G2/M cell cycle arrest, reduced induction of apoptosis and decreased amount of senescent cells. These modified cellular responses appeared mediated by HIF-1α.Conclusion: Our data suggest that targeting hypoxia after irradiation may benefit patients with aggressive hypoxic prostate tumors.

Impact of different grades of microscopic hematuria on the performance of urine-based markers for the detection of urothelial carcinoma - Corrected Proof

2011-12-02

Abstract: Objective: To evaluate the performance of urine cytology (CYT), the UroVysion test [(fluorescence-in-situ-hybridization (FISH)], the uCyt+-test, and the nuclear matrix protein 22 ELISA (NMP22) at different grades of microscopic hematuria (HU) in a cohort of 2,365 patients suspicious for urothelial cell carcinoma (UCC).Patients and methods: A cohort of 2,365 consecutive patients suspected to have UCC underwent testing of at least 1 of the 4 noninvasive urine markers followed by cystoscopy, upper urinary tract imaging and, in case of suspicious findings, transurethral biopsy and/or resection of suspicious lesions. The grade of microscopic HU was determined by dipstick evaluation and urine microscopy and subdivided into 4 grades. The test results were compared with the HU status by contingency analysis and Cochran-Armitage test for trend separated for patients without evidence of UCC and with histologically proven UCC.Results: In case of grade 0, I, II, and III HU, rates of false positive CYT were 13.0, 17.4, 16.3, and 19.5% (P = 0.02), false negative CYT distributed 37.9, 18.5, 20.0, and 15.5% (P = 0.0003). FISH was false positive in 16.7, 19.8, 19.8, and 23.3% (P = 0.051) and false negative in 42.7, 27.5, 25.9, and 25.0% (P = 0.1). The uCyt+ was false positive in 12.5, 16.9, 24.0 and 35.1% (P < 0.0001), and false negative in 57.1, 26.4, 31.5, and 12.7% (P = 0.0003). NMP22 was false positive in 35.3, 55.3, 75.2, and 79.7% (P < 0.0001) and false negative in 50.0, 36.2, 22.6, and 8.2% (P < 0.0001).Conclusion: The extent of microscopic HU significantly influences the performance of noninvasive urine markers for UC. False positive rates of CYT, uCyt+, and NMP22 significantly increase with the degree of HU whereas false negative results of CYT, uCyt+, and NMP22 are less frequent in patients with high grade microscopic HU. These results underline the relevance of the grade of HU for the appropriate interpretation of urine tests.

Early incontinence after radical prostatectomy: A community based retrospective analysis in 911 men and implications for preoperative counseling - Corrected Proof

2011-11-21

Abstract: Introduction: Radical prostatectomy (RP) is curative for localized prostatic cancer. Incontinence after RP (P-RP-I) varies widely (2% to <60%) according to the definition and quantification of incontinence, timing of evaluation, and who evaluates (physician or patient). Conservative treatments, including pelvic floor muscle training (PFMT), anal electrical stimulation (AES), lifestyle adjustment, or combination are usually recommended at first for P-RP-I.Methods: Between January 2002 and December 2004, a total of 911 patients, median age 63years (46–78), with different grades of P-RP-I have been retrospectively examined for perioperative risk factors and effect of rehabilitation procedures. These consecutive patients were from 67 clinics with median postoperative interval of 26 days. Incontinence was graded by Stamey classification, number of used pads and pads' consistency (dry, lightly wet, and wet). Therapeutic measures were done by team of specialists in rehabilitation, psycho-oncology, physiotherapy, internal medicine, and urology.Results: Ninety-six percent of patients suffered different grades of incontinence at beginning of hospitalization. This was reported as Stamey first grade (49.4%), second grade (36.4%), and third grade (10.3%). Analysis included patients' age, body mass index (BMI), prostate volume, surgical approach, nerve sparing, pelvic lymphadenectomy, previous therapy, and catheterization time. Analysis showed age, nerve sparing, and BMI as significant risk factors for P-RP-I. Conservative therapy, including PFMT, AES, or combinations has been performed on all patients. Grade of P-RP-I showed significant improvement after 3weeks rehabilitation period.Conclusion: Preoperative counseling of patients should provide them with realistic expectations for P-RP-I and motivate them to conservative therapy, as it reduces the duration and degree of urinary incontinence.

Discharge patterns after radical prostatectomy in the United States of America - Corrected Proof

2011-11-21

Abstract: Objective: Discharge patterns, including prolonged length of stay (LOS) and adverse discharge disposition (ADD), are important clinical indicators of quality of care. We examined the effect of several indicators on discharge patterns after radical prostatectomy (RP).Methods: Within the Nationwide Inpatient Sample, we focused on RPs performed between 2001 and 2007. Multivariable logistic regression analyses predicting the likelihood of prolonged LOS and ADD were performed.Results: Overall, 89,883 eligible RPs were identified, yielding a weighted national estimate of 442,400 eligible RPs. The rates of prolonged LOS decreased from 28.9 in the early period (2001–2003) to 14.4% in the late period (2006–2007) (P < 0.001). Similarly, the rates of ADD decreased from 7.4 in the early period to 5.0% in the late period (P < 0.001). In multivariable analyses adjusted for clustering, both annual hospital caseload (AHC) and insurance status were independent predictors of prolonged LOS and ADD. For example, RP performed at low AHC hospitals were more frequently associated with prolonged LOS than intermediate (OR = 0.45, P < 0.001) and high (OR = 0.21, P < 0.001) AHC hospitals. Similarly, RP performed at low AHC hospitals were more frequently associated with ADD than intermediate (OR = 0.54, P < 0.001) and high (OR = 0.63, P < 0.001) AHC hospitals.Conclusions: An improving temporal trend in discharge patterns was recorded in patients undergoing RP, with significant reductions in the rates of prolonged LOS and ADD. Nonetheless, important disparities were recorded when discharge patterns were stratified according to insurance status and AHC. Specifically, shorter LOS and lower rates of ADD should be expected in patients with private insurance and/or treated at high AHC institutions.

Adult urologic sarcoma: Experience during 2 decades - Corrected Proof

2011-11-18

Abstract: Objective: To identify factors associated with long-term outcome and to report possibly meaningful clinical features in a unicentric sample of adult urologic sarcomas.Materials and methods: Thirty-five patients treated between 1992 and 2011 were studied. Except for 3 patients, surgery was the initial treatment. The median follow-up in the surviving (censored) patients was 11.3 years. Kaplan-Meier method and competing risk analysis were used to evaluate outcome. Disease recurrence, disease-specific mortality, and overall mortality were the study endpoints. Comparisons were made with the log rank and the Pepe-Mori tests. Cox proportional hazard models were used to identify independent predictors of disease recurrence.Results: Only disease grade was significantly associated with all 3 study endpoints. The primary tumor site was significantly associated with disease-specific and recurrence-free survival but did not reach the significance level concerning overall survival. In the multivariate analysis, primary site and tumor grade were identified as predictors of disease recurrence. Whereas 10-year disease-specific survival was 100% in patients with low grade inguinoscrotal tumors, it was 0% in patients with high grade disease arising from other sites.Conclusions: Low grade and inguinoscrotal origin are factors associated with favorable outcome in urologic sarcomas. Repeat interventions to remove or to inactivate recurrent tumors or metastases seem to provide clinical benefit in individual cases.

Applying narrow-band imaging in complement with white-light imaging cystoscopy in the detection of urothelial carcinoma of the bladder - Corrected Proof

Guangfu Chen, Baojun Wang, Hongzhao Li, Xin Ma, Taoping Shi, Xu Zhang — 2011-11-14

Abstract: Objectives: To investigate the value of narrow-band imaging (NBI) flexible cystoscopy in the detection of urothelial carcinoma (UC) of the bladder.Materials and methods: Clinical data of 179 patients with suspected UC, who presented with gross hematuria, were collected at China PLA General Hospital from January 2009 to August 2010. These patients underwent white-light imaging (WLI) cystoscopy followed by NBI. The tumors were visualized, imaged, and recorded. Suspected UCs were biopsied or treated by transurethral resection, and then sent for pathologic examination. Detection results for NBI and WLI were compared.Results: WLI and NBI confirmed UC in 143 patients; a total of 285 tumors were detected. The patient-level detection rates for NBI and WLI were 97.9% (140/143) and 88.8% (127/143), respectively (P = 0.002). The patient-level false-positive detection rates for NBI and WLI were 21.8% (39/179) and 29.1% (52/179), respectively (P = 0.12). NBI detected a total of 59 additional tumors (17.2%; 34pTa, 17pT1, 3pT2, and 5pTis) in 44 of 143 patients (30.8%). NBI found 1 additional tumor in 34 cases, 2 additional tumors in 6 cases, 3 additional tumors in 3 cases, and 4 additional tumors in 1 case. The mean ± SD (range) number of identified UCs per patient was 1.97 ± 0.67 (1–5) for NBI and 1.78 ± 0.53 (1–4) for WLI (P = 0.01). The tumor-level detection rates for NBI and WLI were 96.8% and 79.3%, respectively (P < 0.001).Conclusions: Compared with WLI, NBI improves UC detection. It has a higher rate of detection and a comparative rate of false-positive detection. NBI is simple and requires no dyeing. It can be conveniently applied to complement WLI.

Comprehensive handbook for developing a bladder cancer cystectomy database - Corrected Proof

2011-11-07

Abstract: Objective: In an effort to standardize data collection for research regarding bladder cancer, the Bladder Cancer Working Group sought to provide a handbook that can be used as a guide for prospective or retrospective data collection.Methods: Expert opinions for various data groups were compiled through a team of researchers at the BCAN. Peer review of each data group was performed from within the group.Results: Essential and comprehensive data elements are provided for 9 groups of data elements, including demographics, comorbidities, staging, laboratory data, operative details, pathology, complications, outcomes, and quality of life measurements.Conclusions: Establishment of a comprehensive bladder cancer database is important in initiating multicenter collaborations. While not every data point is critical, this review may be useful in serving as a reference in initiating projects and providing a framework for collaborations.

Gender-specific differences in cancer-specific survival after radical cystectomy for patients with urothelial carcinoma of the urinary bladder in pathologic tumor stage T4a - Corrected Proof

2011-11-07

Abstract: Background: Bladder cancer (UCB) staged pT4a show heterogeneous outcome after radical cystectomy (RC). No risk model has been established to date. Despite gender-specific differences, no comparative studies exist for this tumor stage.Materials and methods: Cancer-specific survival (CSS) of 245 UCB patients without neoadjuvant chemotherapy staged pT4a, pN0-2, M0 after RC were analyzed in a retrospective multi-center study. Seventeen patients were excluded from further analysis due to carcinoma in situ (CIS) of the prostatic urethra and/or positive surgical margins. Average follow-up period was 30 months (IQR: 14–45). The influence of different clinical and histopathologic variables on CSS was determined through uni- and multivariate Cox regression analyses. Two risk groups were generated using factors with independent effect in multivariate models. Internal validity of the prediction model was evaluated by bootstrapping.Results: Eighty-four percent of the patients (n = 192) were male; 72% (n = 165) showed lymphovascular invasion (LVI). The 5-year CSS rate was 31%, and significantly different between male and female (35% vs. 15%, P = 0.003). Multivariate Cox regression modeling, female gender (HR = 1.83, P = 0.008), LVI (HR = 1.92, P = 0.005), and absence of adjuvant chemotherapy (HR = 0.61, P = 0.020) significantly worsened CSS. Two risk groups were generated using these 3 criteria, which differed significantly between each other in CSS (5-year-CSS: 46% vs. 12%, P < 0.001). The c-index value of the risk model was 0.61 (95% CI: 0.53–0.68, P < 0.001).Conclusions: Prognosis in UCB staged pT4a is heterogeneous. Female gender and LVI are adverse factors. Adjuvant chemotherapy seems to improve outcome. The present analysis establishes the first risk model for this demanding tumor stage.

Intravenous therapies for castration-resistant prostate cancer: Toxicities and adverse events - Corrected Proof

Eric A. Singer, Ramaprasad Srinivasan — 2011-10-20

Abstract: Prostate cancer (CaP) continues to be a significant burden on men's health. While significant advances have been made in the diagnosis and treatment of localized disease, androgen deprivation therapy remains the treatment of choice for advanced and metastatic disease. However, once a man progresses on androgen deprivation, therapies targeting castration-resistant CaP have been extremely limited until quite recently. Urologic oncologists who wish to play an active role in the treatment of men with CaP from diagnosis through end-of-life care should be familiar with administration of and toxicities associated with chemotherapeutic agents. This review is directed at urologists and urologic oncologists and will discuss many of the FDA-approved intravenous agents currently available for castration-resistant CaP with a specific focus on the side-effects associated with these regimens.

NOTCH1 functions as an oncogene by regulating the PTEN/PI3K/AKT pathway in clear cell renal cell carcinoma - Corrected Proof

2011-10-13

Abstract: Objectives: Although NOTCH1 plays a wide-ranging role in controlling cell fate, differentiation, and development, its pathologic roles in clear cell renal cell carcinoma (CCRCC) are still unclear. In the present study, the expression pattern of NOTCH1 was examined in CCRCC tissues, and the interaction of NOTCH1 with the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT pathway was investigated in vitro.Materials and methods: Thirty-six paired CCRCC and adjacent non-neoplastic renal samples were analyzed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The alteration of NOTCH1, hairy and enhancer of split 1 (HES1), PTEN, AKT (phosphorylated at Ser473) in CCRCC cell line (786-O), and the human normal kidney tubule epithelial cell line (HKC) were analyzed by Western blotting and qRT-PCR, before and after transfection with siRNA against NOTCH1 or the plasmid containing the ORF clone of NOTCH1. The effects of NOTCH1 signaling pathway on cells proliferation, apoptosis, invasion, and migration were detected by MTS assay, flow cytometry analyses, and transwell chamber assay, respectively.Results: The NOTCH1 expression levels were significantly increased in CCRCC tissues compared with the adjacent non-neoplastic renal samples, while it had no significant association with the pathologic parameters. NOTCH1 signaling cascade was constitutively active in human CCRCC cell lines. Blocking NOTCH1 signaling resulted in the attenuation of proliferation, invasion, and migration, as well as PTEN up-regulation with decreased AKT phosphorylation. NOTCH1 overexpression had an opposite effect to NOTCH1 knockdown.Conclusions: Our findings indicated that NOTCH1 receptor expression was up-regulated in CCRCC, and that NOTCH1 could regulate PTEN expression and the activity of the PI3K/AKT pathway via HES1 in 786-O and HKC cell lines. These might provide a basis for the designing new therapeutic strategies for CCRCC.

Immunostimulatory CpG-DNA and PSA-peptide vaccination elicits profound cytotoxic T cell responses⁎ - Corrected Proof

2011-10-10

Abstract: Objective: Novel strategies for the treatment of advanced prostate cancer (CaP), including immunotherapy or gene therapy, are currently under evaluation with Sipuleucel-T as first FDA-approved immunotherapeutic. Here, we examine cytosine-phosphorothioate-guanine (CpG)-DNA oligonucleotides (ODN) to boost cytokine responses and costimulatory molecule expression on murine bone marrow-derived dendritic cells (mBMDC). Furthermore, we evaluate the potency of a PSA-peptide based vaccine in combination with CpG-DNA to elicit specific cytotoxic T cell (CTL) responses.Materials and methods: mBMDC were stimulated with CpG-DNA (1668: 5′-TCCATGACGTTCCTGATGCT-3′) or non-stimulatory control-ODN (1720: 5′-TCCATGAGCTTCCTGATGCT-3′). Subsequently, expression of the costimulatory molecules CD40 and CD86 and induction of proinflammatory cytokines (interleukin (IL)-6 and IL-12) were analyzed. For induction of PSA-peptide specific CTL, female C57BL/6 mice were immunized with PSA-peptide 65–73 (HCIRNKSVI) alone or in combination with 1668 or 1720-ODN. In vivo cytotoxicity assay determined PSA-peptide specific cytotoxicity 1 week after vaccination.Results: Treatment of mBMDC with stimulatory CpG-DNA ODN resulted in pronounced up-regulation of costimulatory molecule expression on mBMDC in a dose-dependent manner. CpG-ODN significantly increased production of IL-6 and IL-12 in mBMDC (P < 0.001). Induction of PSA-peptide specific CTL responses in mice immunized with PSA-peptide and CpG-DNA were significantly greater than those of PSA-peptide and control-ODN immunized mice or PSA-peptide only vaccination.Conclusions: CpG-DNA acts as potent adjuvant for vaccination therapies and elicits profound PSA-peptide specific CTL responses in combination with an immunodominant PSA-peptide. CpG-ODN mediated immunotherapy represents a potentially inexpensive, safe, easy-to-produce, and easy-to-handle treatment alternative. Therefore, further evaluation of CpG-DNA in immunization therapies against CaP is warranted.

Lymph vessel density in seminomatous testicular cancer assessed with the specific lymphatic endothelium cell markers D2-40 and LYVE-1: Correlation with pathologic parameters and clinical outcome - Corrected Proof

2011-10-05

Abstract: Objectives: To evaluate the role of lymph vessel density (LVD) and lymphangiogenesis in seminomatous testicular cancer (STC) by using the lymphatic endothelial cell (LEC) markers LYVE-1 and D2-40.Methods and materials: Paraffin embedded tumor specimens from 40 patients with STC were stained by specific D2-40 and Lyve-1 antibodies. LVD was measured in different representative and standardized areas. Fluorescence double immunostaining for Lyve-1 and Ki-67 was performed and results were correlated with clinicopathologic data. The median follow-up period was 55 (range 10–135) months.Results: Mean intratumoral LVD (D2-40: 1.30 ± 1.99; Lyve-1: 1.82 ± 2.34) was significantly lower than peritumoral LVD (D2-40: 4.94 ± 2.58; Lyve-1: 4.62 ± 2.73) and LVD in nontumoral areas (D2-40: 4.81 ± 3.79; Lyve-1: 4.22 ± 3.19). There was no significant difference between LVD measures when using D2-40 or LYVE-1. Detection rates of lymphatic vascular invasion (LVI) were significantly higher than in conventional HE-stained sections (77.5% vs. 52.5%). No proliferating lymphatic vessels were found.Conclusions: We found that LVD is decreased within tumor areas of STC. Despite a higher peritumoral LVD, no signs of proliferating endothelial cells were observed, suggesting a lack of lymphangiogenesis in STC. Detection of LVI can be optimized by specific D2-40 or LYVE-1 staining.

Investigation of tumor suppressor genes apart from VHL on 3p by deletion mapping in sporadic clear cell renal cell carcinoma (cRCC) - Corrected Proof

Rashmi Bhat Singh, Pratibha S. Amare Kadam — 2011-10-03

Abstract: Objectives: To investigate the most recurrent deletion loci on 3p12-p26 by deletion mapping studies by PCR-LOH and BAC array-FISH in sporadic conventional renal cell carcinoma (cRCC) and further, to evaluate the their clinicopathologic significance in cRCC. Comparative allelotyping studies in cRCC and major epithelial carcinomas (MEC) such as lung, breast, and bladder tumors were also carried out to investigate the specificity of the targeted loci in cRCC.Subjects and methods: A total of 40 c-RCC patients were enrolled in this study, categorized in to 2 groups: group I comprises of patients of stages I and II and group II includes patients at stages III and IV. Loss of heterozygosity (LOH) studies were performed by PCR using 15 microsatellite markers of region 3p12-p26 on paired normal-tumor tissues. The recurrent LOH loci found in 27 cRCC tumors were further validated by BAC array-FISH using 23 serially mapped BAC clones. Simultaneously, the allelic deletion status of fragile histidine triad (FHIT) gene was studied by FISH in cRCC and major epithelial carcinoma (MEC) tumors. The numerical aberrations of chromosome 3 were also studied using the centromere enumeration probe (CEP) probe for chromosome 3 to validate the observed allelic losses by BAC array-FISH in cRCC as well as MECs.Results: Our study revealed 3 affected regions of LOH on 3p in cRCC: 3p12.2-p14.1, 3p14.2-p21.1, and 3p24.2-p26.1 in both group I (stages I and II) and group II (stage III and IV). Comparative allelotyping studies revealed that except for LOH loci D3S2406 (20%), D3S1766 (14%), and D3S1560 (20%), remaining affected loci revealed retention of heterozygosity (ROH) in breast carcinomas. Lung and bladder tumors revealed ROH at all affected LOH loci. FISH with FHIT gene probe revealed deletions in cRCC (88%), breast (30%), and lung tumors (10%). FHIT gene deletions frequency was almost equal in both groups I and II (>70%), whereas a locus 3p13 (D3S2454) revealed the highest LOH in group II (83%) patients in comparison to group I (16%). BAC array-FISH studies in cRCC identified 15 recurrent deletion loci at crucial regions, 3p12.2, 3p14.2, 3p21.3, and 3p24.2-p26 with long continuous deletion of 3p14.1-p26.1 exclusively in patients of stages III and IV. Validation of LOH loci in breast carcinomas by BAC array-FISH with BAC clones mapped at these loci revealed comparatively lower deletion frequency for RP11-59E22 (3p12.2) (30%), RP11-759B7(3p21.1) (12%), and RP11-57D6 (3p25.2, proximal to VHL) (15%) than cRCC.Conclusion: Molecular cytogenetic studies by BAC array-FISH was found to be more sensitive over LOH. Deletion patterns on 3p explored that deletion of FHIT and flanking loci may occur as an initiating event followed by deletions at 3p12.2, 3p21.31–3p21.32, and 3p24.2–3p26.1 in the initial stage of development of disease, while continuous large deletions of 3p21.3–3p26.1 and 3p14.1–3p26.1 occur as progressive deletion due to genetic instability. Lack of VHL along with flanking loci in 50% cRCC patients that included both groups I and II supported the hypothesis of both VHL dependent and VHL independent pathways in cRCC tumorigenesis. Comparative allelotyping studies in cRCC and MECs indicated association of specific targeted loci including VHL in cRCC. Further expansion of these studies with characterization of the genes at targeted loci and correlation with clinical outcome will explore the prognostic significance and also provide an insight into the mechanisms of tumor suppressive pathways in genitourinary cancers such as CRCC.

Is Memorial Sloan-Kettering Cancer Center risk classification appropriate for Japanese patients with metastatic renal cell carcinoma in the cytokine era? - Corrected Proof

2011-09-28

Abstract: Objectives: We investigated the prognosis of Japanese patients with metastatic renal cell carcinoma (RCC), and analyzed the validity of Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification.Materials and methods: The endpoint of the present study was overall survival. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model with a step-wise procedure. Prognostic assessment was also performed according to the MSKCC risk classification. The predictive accuracy of the MSKCC risk classification was measured employing the concordance index.Results: The median survival for all patients was 22 months (95% CI, 19–28 months). The eight factors were identified as independent prognostic factor; time from initial diagnosis to metastasis, low hemoglobin (Hb), lactate dehydrogenase (LDH), corrected serum calcium (cCa), C-reactive protein (CRP), and the presence or absence of liver metastasis, bone metastasis, and lymph node metastasis. When the MSKCC risk classification was applied to patients, the median overall survival was not reached and 26 and 10 months in the patients classified as favorable, intermediate, and poor risk, respectively. The c-index was 0.73.Conclusions: The prognosis of Japanese metastatic renal cell carcinoma patients may be better than that of previous studies from North America or Europe. Although there are some differences in the rate of patients in the risk groups and survival time by risk group between these patients, the MSKCC risk classification may be applicable for Japanese patients with metastatic renal cell carcinoma.

Utilizing pre-therapy clinical schema and initial CT changes to predict progression-free survival in patients with metastatic renal cell carcinoma on VEGF-targeted therapy: A preliminary analysis - Corrected Proof

2011-09-28

Abstract: Objective: Because of varying treatment effectiveness with vascular endothelial growth factor (VEGF)-targeted therapy in patients with metastatic renal cell carcinoma (RCC), the association of prognostic pre-therapy clinical schema, initial post-therapy computed tomography (CT) findings, and combination thereof in predicting progression-free survival (PFS) was investigated. A predictive biomarker that combines clinical risk factors and CT imaging features associated with initial response to therapy would be useful in stratifying patients into risk groups to guide therapy, in designing and interpreting results of clinical trials, in planning risk-directed therapy, and in patient counseling. Early identification of poor responders using an imaging biomarker may reduce drug-related toxicity and cost and allow for a therapeutic intervention before disease burden significantly advances.Materials and methods: For this institutional review board-approved HIPAA-compliant retrospective study, baseline data for 82 patients with metastatic RCC treated with sunitinib or sorafenib was obtained for risk stratification by Memorial Sloan Kettering Cancer Center (MSKCC) criteria and criteria by Heng et al. (J Clin Oncol 2009;27:5794–9), (described here as “VEGF prognostic factors criteria”). The initial post-therapy CT was evaluated by Response Assessment Criteria in Solid Tumors (RECIST), Choi criteria, and Morphology, Attenuation, Size, and Structure (MASS) criteria. Kaplan-Meier estimates of PFS (the reference standard) for each patient group and overall accuracy of each method and combined criteria were calculated.Results: The MSKCC model, VEGF prognostic factors criteria, RECIST, MASS criteria, MSKCC + MASS criteria, and VEGF prognostic factors + MASS criteria each demonstrated significant differences in PFS among patient groups (P < 0.005 for each, Log-rank test). Stratification of patient groups by Choi criteria was not statistically significant with respect to PFS (P = 0.101). MSKCC + MASS criteria yielded the highest overall accuracy for identifying PFS ≥ 1 year (77%) and for identifying PFS < 1 year (77%).Conclusions: A combination of pre-therapy clinical risk factors and CT imaging response by MASS criteria more effectively predicted PFS in patients with metastatic RCC on VEGF-targeted therapy than any single method.

When urothelial differentiation pathways go wrong: Implications for bladder cancer development and progression - Corrected Proof

2011-09-19

Abstract: Differentiation is defined as the ability of a cell to acquire full functional behavior. For instance, the function of bladder urothelium is to act as a barrier to the diffusion of solutes into or out of the urine after excretion by the kidney. The urothelium also serves to protect the detrusor muscle from toxins present in stored urine. A major event in the initiation and progression of bladder cancer is loss of urothelial differentiation. This is important because less differentiated urothelial tumors (higher histologic tumor grade) are typically associated with increased biologic and clinical aggressiveness. The differentiation status of urothelial carcinomas can be assessed by histopathologic examination and is reflected in the assignment of a histologic grade (low-grade or high-grade). Although typically limited to morphologic evaluation in most routine diagnostic practices, tumor grade can also be assessed using biochemical markers. Indeed, current pathological analysis of tumor specimens is increasingly reliant on molecular phenotyping. Thus, high priorities for bladder cancer research include identification of (1) biomarkers that will enable the identification of high grade T1 tumors that pose the most threat and require the most aggressive treatment; (2) biomarkers that predict the likelihood that a low grade, American Joint Committee on Cancer stage pTa bladder tumor will progress into an invasive carcinoma with metastatic potential; (3) biomarkers that indicate which pTa tumors are most likely to recur, thus enabling clinicians to prospectively identify patients who require aggressive treatment; and (4) how these markers might contribute to biological processes that underlie tumor progression and metastasis, potentially through loss of terminal differentiation. This review will discuss the proteins associated with urothelial cell differentiation, with a focus on those implicated in bladder cancer, and other proteins that may be involved in neoplastic progression. It is hoped that ongoing discoveries associated with the study of these differentiation-promoting proteins can be translated into the clinic to positively impact patient care.

Sequential administration of GM-CSF and IL-2 surface-modified MB49 cells vaccines against the metastatic bladder cancer - Corrected Proof

2011-09-19

Abstract: Objectives: Many strategies are pursued to enhance tumor vaccine immune response, including the utilization of cytokines. We have developed a novel protein-anchor technology to immobilize cytokines on tumor cell surface. Here we reported the preparation of tumor cell vaccines by immobilizing GM-CSF or IL-2 on MB49 bladder cancer cells and evaluated their antitumor efficacy (administrated alone or sequentially) in a metastatic mouse model.Materials and methods: SA-mGM-CSF or SA-hIL-2 surface-modified MB49 cells were prepared as vaccine. Mice were treated with MB49 cell vaccines (administrated alone or sequentially). Survival time, tumor growth, flow cytometry, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and cytotoxic T lymphocytes (CTL) assay were used to evaluate the antitumor efficiency of the vaccines in the pulmonary metastatic model of bladder cancer.Results: GM-CSF vaccine induced more mature dendritic cells in the mice spleen. Combination with subsequent IL-2 vaccine significantly increased CD4+, CD8+, and IFN-γ+CD8+ T but not CD4+Foxp3+ T cell population and induced the highest production of IFN-γ, IL-12, but not IL-10. Furthermore, the splenocytes from the sequentially combined vaccines group showed the most potent cytotoxicity on MB49 cells. Finally, the sequentially combined vaccines evidently extended the survival time of mice (the median survival time of PBS, ethanol-fixed, anchored GM-CSF, anchored IL-2, and anchored GM-CSF + anchored IL-2 groups were 34, 37, 45, 47, and 59 days, respectively) and effectively protected the mice against a second MB49 cells but not RM-1 cells challenge.Conclusions: This study demonstrated that sequential administration of GM-CSF and IL-2 surface-modified MB49 cells vaccines could effectively induce specific antitumor immune response.

Abdominal obesity as risk factor for prostate cancer diagnosis and high grade disease: A prospective multicenter Italian cohort study - Corrected Proof

2011-09-19

Abstract: Objective: To evaluate the association between abdominal obesity and prostate cancer (CaP) diagnosis and grade in patients undergoing prostate biopsy.Materials and methods: Between 2008 and 2011, we prospectively enrolled patients referred to 3 clinics in Italy who were scheduled for transrectal ultrasound (TRUS) guided prostate biopsy. Before biopsy, digital rectal examination (DRE), prostate specific antigen (PSA), body mass index (BMI), and waist circumference (WC) were measured. Men were categorized in 4 groups of body habitus, according to BMI and waist circumference values. Crude and adjusted logistic regressions were performed to assess the association of BMI (continuous), waist circumference (continuous), body habitus (categorical), and CaP diagnosis and grade.Results: Six hundred sixty-eight patients were enrolled. CaP was detected in 246 patients (38%), of whom 136 had low-grade (Gleason score ≤ 6) and 110 high-grade cancer (Gleason score ≥ 7). Logistic regression multivariate analysis showed that BMI (OR 1.05 per unit, CI 95% 1.00–1.10 P = 0.033) and waist circumference (OR 1.02 per cm, CI 95% 1.00–1.04 P = 0.026) were significant predictors of CaP diagnosis. BMI (OR 1.11 95% CI 1.04–1.18 P = 0.001) and WC (OR 1.04 95% CI 1.02–1.06 P = 0.001) were also associated with high-grade CaP. Furthermore, obesity with central adiposity (BMI ≥ 30kg/m2 and WC ≥ 102 cm) was significantly associated with CaP diagnosis (OR 1.66, CI 95% 1.05–2.63, P = 0.03) and high-grade disease (OR 2.56, CI 95% 1.38–4.76, P = 0.003).Conclusions: Obesity defined by BMI and WC seems to be associated with CaP and, more specifically, with high-grade disease at the time of biopsy. The relationship between obesity and CaP is complex and remains to be further addressed.