Raj Persad

A Review of Current Guidelines and Best Practice Recommendations for the Management of Nonmuscle Invasive Bladder Cancer by the International Bladder Cancer Group

PURPOSE Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories. MATERIALS AND METHODS An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010. RESULTS Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer. CONCLUSIONS Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression.

Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells.

Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA–Rho–Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.

Are diet-prostate cancer associations mediated by the IGF axis? A cross-sectional analysis of diet, IGF-I and IGFBP-3 in healthy middle-aged men

We examined the association of diet with insulin-like growth factors (IGF) in 344 disease-free men. Raised levels of IGF-1 and/or its molar ratio with IGFBP-3 were associated with higher intakes of milk, dairy products, calcium, carbohydrate and polyunsaturated fat; lower levels with high vegetable consumption, particularly tomatoes. These patterns support the possibility that IGFs may mediate some diet–cancer associations.

Sildenafil inhibits the formation of superoxide and the expression of gp47phox NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells

To assess the effect of sildenafil on superoxide formation and p47phox (the active subunit of NADPH oxidase) expression in cultured corpus cavernosal smooth muscle cells (CVSMCs).

Investigating Black-White differences in prostate cancer prognosis: A systematic review and meta-analysis

The case‐fatality rate following a diagnosis of prostate cancer is higher for Black men compared to White men. How this elevated rate arises is uncertain, with differences in disease biology, presentation, treatment and comorbidity having been suggested. A systematic search was conducted for articles that reported ethnic differences in overall‐survival, prostate cancer specific survival (PSS) or biochemical recurrence. 48 articles met the inclusion criteria. Black men had worse overall survival (risk ratio 1.35, 95% CI 1.23–1.48) but this was not due to comorbidity alone as PSS and risk of biochemical recurrence were also elevated (1.29, 95% CI 1.13–1.47 and 1.34, 95% CI 1.23–1.46, respectively). Studies adjusting for clinical predictors and socioeconomic variables no longer supported a difference in overall survival (1.01, 95% CI 0.88–1.16), but continued to find an increased risk amongst Black men for PSS (1.13, 95% CI 1.00–1.27) and biochemical recurrence (1.25, 95% CI 1.11–1.41). Similar results were seen for studies from the pre‐PSA era and free‐health care settings. In contrast to others, studies of metastatic cancer did not find evidence of Black‐White differences (p for interaction = 0.01). In conclusion, Black men had a poorer prognosis which was not fully explained by comorbidity, PSA screening, or access to free health care, although few studies measure these factors well. Either management differences for local disease and/or biological differences may be behind Black‐White differences in prostate cancer prognosis.

Scoring systems used for the interpretation and reporting of multiparametric MRI for prostate cancer detection, localization, and characterization: could standardization lead to improved utilization of imaging within the diagnostic pathway?

Multiparametric magnetic resonance imaging (mpMRI) is increasingly being used earlier in the prostate cancer diagnostic pathway in order to detect and localize disease. Its results can be used to help decide on the indication, type, and localization of a prostate biopsy for cancer diagnosis. In addition, mpMRI has the potential to contribute information on the characterization, or aggressiveness, of detected cancers including tumor progression over time. There is considerable variation in the way results of different MRI sequences are reported. We conducted a review of scoring systems that have been used in the detection and characterization of prostate cancer. This revealed that existing scoring and reporting systems differ in purpose, scale, and range. We evaluate these differences in this review. This first step in collating all methods of scoring and reporting mpMRI will ultimately lead to consensus approaches to develop a standardized reporting scheme that can be widely adopted and validated to ensure comparability of research outputs and optimal clinical practice. J. Magn. Reson. Imaging 2013;37:48–58.

Effect of hydrogen sulphide-donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats

To study the effect of the H2S‐donating derivative of sildenafil (ACS6) compared to sildenafil citrate and sodium hydrosulphide (NaHS) on relaxation, superoxide formation and NADPH oxidase and type 5 phosphodiesterase (PDE5) expression in isolated rabbit cavernosal tissue and smooth muscle cells (CSMCs), and in vivo on indices of oxidative stress induced with buthionine sulphoximine (BSO).

Screen-detected prostate cancer and the insulin-like growth factor axis: results of a population-based case-control study.

Higher circulating levels of IGF‐I have been associated with increased risk of prostate and some other cancers. Most research on prostate cancer has been based on men with symptoms or identified following treatment of benign disease. However, increasing numbers of cancer cases are now detected in asymptomatic men following prostate‐specific antigen (PSA) tests. We therefore used a population‐based case‐finding exercise using the PSA test to examine whether associations between the IGF axis and cancer risk were apparent in this population. A matched case‐control study was conducted among 7,383 men (50–70 years) receiving a PSA test as part of a case‐finding exercise. Assays of IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3 were performed on cases and 2 controls matched on age, recruitment center and calendar time. Analyses were based on 176 cases and 324 matched controls. The risk of prostate cancer increased across quartiles of IGF‐I (highest vs. lowest quartile, OR = 2.34; 95% CI = 1.26–4.34; ptrend = 0.02) and IGF‐II (OR = 1.78; 95% CI = 0.94–3.15; ptrend = 0.09). Controlling for smoking history and IGFBP‐3 strengthened associations with cancer for both IGF‐I (OR = 3.00; 95% CI = 1.50–6.01; ptrend 0.005) and IGF‐II (OR = 2.02; 95% CI = 1.07–3.84; ptrend = 0.04) Associations between the IGFs and cancer risk were stronger for advanced cases. Our findings suggest that both IGF‐I and IGF‐II are associated with an increased risk of screen‐detected prostate cancer.

Definitions, End Points, and Clinical Trial Designs for Non–Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group

PURPOSE To provide recommendations on appropriate clinical trial designs in non-muscle-invasive bladder cancer (NMIBC) based on current literature and expert consensus of the International Bladder Cancer Group. METHODS We reviewed published trials, guidelines, meta-analyses, and reviews and provided recommendations on eligibility criteria, baseline evaluations, end points, study designs, comparators, clinically meaningful magnitude of effect, and sample size. RESULTS NMIBC trials must be designed to provide the most clinically relevant data for the specific risk category of interest (low, intermediate, or high). Specific eligibility criteria and baseline evaluations depend on the risk category being studied. For the population of patients for whom bacillus Calmette-Guérin (BCG) has failed, the type of failure (BCG unresponsive, refractory, relapsing, or intolerant) should be clearly defined to make comparisons across trials feasible. Single-arm designs may be relevant for the BCG-unresponsive population. Here, a clinically meaningful initial complete response rate (for carcinoma in situ) or recurrence-free rate (for papillary tumors) of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months is recommended. For other risk levels, randomized superiority trial designs are recommended; noninferiority trials are to be used sparingly given the large sample size required. Placebo control is considered unethical for all intermediate- and high-risk strata; therefore, control arms should comprise the current guideline-recommended standard of care for the respective risk level. In general, trials should use time to recurrence or recurrence-free survival as the primary end point and time to progression, toxicity, disease-specific survival, and overall survival as potential secondary end points. Realistic efficacy thresholds should be set to ensure that novel therapies receive due review by regulatory bodies. CONCLUSION The International Bladder Cancer Group has developed formal recommendations regarding definitions, end points, and clinical trial designs for NMIBC to encourage uniformity among studies in this disease.

A comparative study of the analysis of human urine headspace using gas chromatography–mass spectrometry

First-void urine samples were obtained from 24 elderly, asymptomatic men (median age 62.9 years). The headspace above pH adjusted urine samples were extracted using a carboxen/polydimethylsiloxane solid phase micro-extraction fibre and the volatile organic compounds analysed by gas chromatography/mass spectrometry. A total of 147 compounds were identified in the headspace of urine. The acidified samples recorded a total of 92 compounds, 27 of which were ubiquitous, basified samples 70 compounds, with 12 ubiquitous and unmodified pH samples 49, with 6 ubiquitous. Five compounds were ubiquitous irrespective of pH: acetone, methylene chloride, 4-heptanone, 2-pentanone and 2-butanone. A comparative analysis of unfrozen and frozen-thawed urine (stored at room temperature for 0, 1 and 8 h) showed that samples retained the same number of compounds although variations in the peak areas for some compounds were observed.