Bladder Cancer

Context: The incidence of bladder cancer increases with advancing age. Considering the increasing life expectancy and the increasing proportion of elderly people in the general population, radical cystectomy will be considered for a growing number of elderly patients who suffer from muscle-invasive or recurrent bladder cancer. Objective: This article reviews contemporary complication and mortality rates after radical cystectomy in elderly patients and the relationship between age and short-term outcome after this procedure. Evidence acquisition: A literature review was performed using the PubMed database with combinations of the following keywords cystectomy, elderly, complications, and comorbidity. English-language articles published in the year 2000 or later were reviewed. Papers were included in this review if the authors investigated any relationship between age and complication rates with radical cystectomy for bladder cancer or if they reported complication rates stratified by age groups. Evidence synthesis: Perioperative morbidity and mortality are increased and continence rates after orthotopic urinary diversion are impaired in elderly patients undergoing radical cystectomy. Complications are frequent in this population, particularly when an extended postoperative period (90 d instead of 30 d) is considered. Conclusions: Although age alone does not preclude radical cystectomy for muscleinvasive or recurrent bladder cancer or for certain types of urinary diversion, careful surveillance is required, even after the first 30 d after surgery. Excellent perioperative management may contribute to the prevention of morbidity and mortality of radical cystectomy, supplementary to the skills of the surgeon, and is probably a reason for the better perioperative results obtained in high-volume centers.

Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub-to low-mg/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for $60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/ inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research. #

Tagetes erecta, Cosmos sulphureus, Antigonon leptopus and Bougainvillea glabra are edible flowers frequently used by the ethnic population of northern Thailand for preparation of salads and flower teas. The main constituents of ethanolic extracts of these flowers, identified with the help of a high-performance liquid chromatography (HPLC) method, were phenolic acids and flavonoids. T. erecta flowers contained the highest level of phenolic compounds, 1107.5 mg/100 g dry weight (DW), which was 3-to 4-fold the level of phenolic compounds in three other flowers evaluated in this study. Lyophilised aqueous extract of T. erecta had the highest Folin-Ciocalteu value (212 ± 9.0 mgGAE/g DW) and exhibited the highest total reducing capacity (Ferric Reducing Antioxidant Power, FRAP assay; 329.4 ± 21.8 μmol Fe 2+ /g DW) and cellular antioxidant activity (CAA assay; EC 50 = 413 μg/ml). However A. leptopus extract exhibited a superior oxygen free radical scavenging ability (oxygen radical absorbance capacity, ORAC-H assay). The extracts were evaluated for their abilities to suppress the proliferation of human cancer cells associated with the digestion system and to inhibit the activity of two enzymes, α-glucosidase and pancreatic lipase. A pronounced anti-proliferative activity against the colorectal adenocarcinoma (HT-29) cells exhibited T. erecta extract (IC 50 = 1.5 mg/ml), while A. leptopus was most active against the gastric adenocarcinoma (AGS) (IC 50 = 0.2 mg/ml) and bladder cancer cells (BL-13) (IC 50 = 0.9 mg/ml). T. erecta extract was identified as an efficient inhibitor of α-glucosidase enzyme (IC 50 = 0.06 mg/ml). T. erecta, C. sulphureus and B. glabra extracts equally inhibited the activity of pancreatic lipase (IC 50 : 4.82 and 4.60 mg/ml, respectively). The results obtained in this study for the first time identified a number of potential health-enhancing properties of aqueous extracts obtained from edible flowers consumed by the indigenous people of Thailand.

The key points of the latest World Health Organization (WHO) classification of non-invasive urothelial tumors are: the description of the categories has been expanded in the current version to improve their recognition; one group (papillary urothelial neoplasm of low malignant potential) with particularly good prognosis does not carry the label of 'cancer'; it avoids use of ambiguous grading such as grade 1/2 or 2/3 (according to the WHO classification published in 1973, i.e., 1973 WHO classification); the group of non-invasive high grade carcinoma is large enough to contain virtually all those tumors that have biological properties (and a high level of genetic instability) similar to those seen in invasive urothelial carcinoma. This scheme is meant to replace the 1973 WHO classification. Changes in classification have their own inherent problems, tending to lead to confusion, at least for a period of time. From the practical point of view, the use of both the 1973 and the latest WHO classifications is recommended until the latter is sufficiently validated. #

Chlorine is by far the most commonly used chemical for the disinfection of water supplies in North America. However, chlorine reacts with organic material in the raw water producing a number of halogenated hydrocarbon by-products. This population-based case-control study in Ontario, Canada examined the relationship between bladder cancer and exposure to chlorination by-products in public water supplies. Residence and water source histories and data from municipal water supplies were used to estimate individual exposure according to water source, chlorination status, and by-product levels (represented by trihalomethane [THM] concentration). Exposures were estimated for the 40-year period prior to the interview, using 696 cases diagnosed with bladder cancer between 1 September 1992 and 1 May 1994 and 1,545 controls with at least 30 years of exposure information. Odds ratios (OR) adjusted for potential confounders were used to estimate relative risk. Those exposed to chlorinated surface water for 35 or more years had an increased risk of bladder cancer compared with those exposed for less than 10 years (OR = 1.41, 95 percent confidence interval [CI] = 1.10-1.81). Those exposed to an estimated THM level > 50 lag/liter for 35 or more years had 1.63 times the risk of those exposed for less than 10 years (CI = 1.08-2.46). These results indicate that the risk of bladder cancer increases with both duration and concentration of exposure to chlorination by-products, with population attributable risks of about 14 to 16 percent. Chlorination by-products represent a potentially important risk factor for bladder cancer.

Contamination of drinking water by nitrate is an evolving public health concern since nitrate can undergo endogenous reduction to nitrite, and nitrosation of nitrites can form N-nitroso compounds, which are potent carcinogens. We conducted an ecologic study to determine whether nitrate levels in drinking water were correlated with non-Hodgkin lymphoma and cancers of the digestive and urinary tracts in an agricultural district (Trnava District; population 237,000) of the Slovak Republic. Routinely collected nitrate data (1975^1995) for villages using public water supplies were computerized, and each village was categorized into low (0^10 mg/L), medium (10.1^20 mg/L), or high (20.1^50 mg/L) average levels of total nitrate in drinking water. Observed cases of cancer in each of these villages were ascertained through the district cancer registry for the time period 1986^1995. Standardized incidence ratios (SIRs) and 95% con¢dence intervals (CI) for all cancer and selected cancer sites were calculated by indirect standardization using age-and sex-speci¢c incidence rates from the entire district. For all cancer in women, SIRs increased from villages with low (SIR=0.87; 95% CI 0.72^0.95) to medium (SIR=1.07; 95% CI 1.00^1.13) to high (SIR=1.14; 1.06^1.22) levels of nitrate (P for trend o0.001); there was a similar trend for all cancer in men from low (SIR=0.90; 95% CI 0.810

Bacillus Calmette-Guerin is the most effective therapy for nonmuscle invasive bladder cancer. Recently to calculate the risks of recurrence and progression based on data from 7 European Organisation for Research and Treatment of Cancer trials a scoring system was reported. However, in that series only 171 patients were treated with bacillus Calmette-Guerin. We developed a risk stratification model to provide accurate estimates of recurrence and progression probability after bacillus Calmette-Guerin.Data were analyzed on 1,062 patients treated with bacillus Calmette-Guerin and included in 4 Spanish Urological Club for Oncological Treatment trials. Stepwise multivariate Cox models were used to determine the effect of prognostic factors. In each patient the weight of all factors was summed to a total score. Patients were then divided into groups, and cumulative recurrence and progression rates were calculated.A scoring system was calculated with a score of 0 to 16 for recurrence and 0 to 14 for progression. Patients were categorized into 4 groups by score, and recurrence and progression probabilities were calculated in each group. For recurrence the variables were gender, age, grade, tumor status, multiplicity and associated Tis. For progression the variables were age, grade, tumor status, T category, multiplicity and associated Tis. For recurrence calculated risks using Spanish Urological Club for Oncological Treatment tables were lower than those obtained with Sylvester tables. For progression probabilities were lower in our model only in patients with high risk tumors.We propose a scoring model to stratify the risk of recurrence and progression in patients treated with bacillus Calmette-Guerin.

Background: Exposure to disinfection byproducts in drinking water has been associated with an increased risk of bladder cancer. We pooled the primary data from 6 case-control studies of bladder cancer that used trihalomethanes as a marker of disinfection byproducts. Methods: Two studies were included from the United States and one each from Canada, France, Italy, and Finland. Inclusion criteria were availability of detailed data on trihalomethane exposure and individual water consumption. The analysis included 2806 cases and 5254 controls, all of whom had measures of known exposure for at least 70% of the exposure window of 40 years before the interview. Cumulative exposure to trihalomethanes was estimated by combining individual year-by-year average trihalomethane level and daily tap water consumption. Results: There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 g/L (ppb) trihalomethanes compared with those who had lower or no exposure (95% confidence interval [CI] ϭ 1.09 -1.41). Estimated relative risks increased

Context: This review focuses on the prevention and management of complications following radical cystectomy (RC) for bladder cancer (BCa). Objective: We review the current literature and perform an analysis of the frequency, treatment, and prevention of complications related to RC for BCa. Evidence acquisition: A Medline search was conducted to identify original articles, reviews, and editorials addressing the relationship between RC and short-and long-term complications. Series examined were published within the past decade. Large series reported on multiple occasions (Lee [1], Meyer [2], and Chang and Cookson [3]) with the same cohorts are recorded only once. Quality of life (QoL) and sexual function were excluded. Evidence synthesis: The literature regarding prophylaxis, prevention, and treatment of complications of RC in general is retrospective, not standardised. In general, it is of poor quality when it comes to evidence and is thus difficult to synthesise. Conclusions: Progress has been made in reducing mortality and preventing complications of RC. Postoperative morbidity remains high, partly because of the complexity of the procedures. The issues of surgical volume and standardised prospective reporting of RC morbidity to create evidence-based guidelines are essential for further reducing morbidity and improving patients' QoL.

A survey of the usage patterns of the artificial sweetener, saccharin, in edible products and a study of its intake pattern in different population groups has been carried out. Of the different edible commodities, ice candy (87 samples) and crushed ice (14 samples), commonly consumed by children, and pan masala (16 samples) and pan flavourings (10 samples), consumed by the habitual population, were collected from different areas of Lucknow, India. Saccharin was extracted from the samples according to an AOAC method and analysed by HPLC. The consumption pattern of ice candy and crushed ice was determined for 6-20 year olds from a household dietary survey using the food frequency recall method (414 families having 1039 subjects). The consumption of pan masala and pan was assessed by a survey of habitual adult consumers comprising 782 and 1141 subjects, respectively. The average and maximum amounts of saccharin in pan masala samples were 12 750 and 24 300 mg kg À1 , respectively, which are 1.6-and 3-fold higher than the maximum permitted levels allowed under Prevention of Food Adulteration (PFA) Act of India. In pan flavourings, the average and maximum amount of saccharin was 12.2 and 20.1%, i.e. 1.52-and 2.5-fold higher than the permissible limits of the PFA Act. The samples of ice candy and crushed ice showed average and maximum levels of 200 and 700 mg kg À1 and 280 and 460 mg kg À1 , respectively. The average intake of saccharin through ice candy and crushed ice was less than 21% of the acceptable daily intake (ADI) (5 mg kg À1 body weight (bw) day À1 ). However, the maximum intake of saccharin, especially in the 6-10-year age group, contributed 57 and 68% of the ADI through ice candy and crushed ice, respectively. Maximum consumption of saccharin in all the age groups, if consuming both ice candy and crushed ice, results in exceeding the ADI by 54% for subjects in the 6-10-year age group. Hence, the 6-10-year age group population may be at risk of exceeding the ADI for saccharin. The average and maximum theoretical daily intake of saccharin through pan masala alone was 1.84 and 13.33 mg kg À1 bw day À1 , contributing 37 and 267% of the ADI, whereas the estimated (maximum) daily intake was 810% of the ADI. The estimated maximum daily intake (EDI) of saccharin through pan was 6.87 mg kg À1 bw day À1 , which was 137% of the ADI. Thus, individuals in the maximum consumption group for pan masala or pan may be susceptible to toxic effects of saccharin, including bladder distention, elevated urine osmolality and bladder cancer.

Tagetes erecta, Cosmos sulphureus, Antigonon leptopus and Bougainvillea glabra are edible flowers frequently used by the ethnic population of northern Thailand for preparation of salads and flower teas. The main constituents of ethanolic extracts of these flowers, identified with the help of a high-performance liquid chromatography (HPLC) method, were phenolic acids and flavonoids. T. erecta flowers contained the highest level of phenolic compounds, 1107.5 mg/100 g dry weight (DW), which was 3-to 4-fold the level of phenolic compounds in three other flowers evaluated in this study. Lyophilised aqueous extract of T. erecta had the highest Folin-Ciocalteu value (212 ± 9.0 mgGAE/g DW) and exhibited the highest total reducing capacity (Ferric Reducing Antioxidant Power, FRAP assay; 329.4 ± 21.8 μmol Fe 2+ /g DW) and cellular antioxidant activity (CAA assay; EC 50 = 413 μg/ml). However A. leptopus extract exhibited a superior oxygen free radical scavenging ability (oxygen radical absorbance capacity, ORAC-H assay). The extracts were evaluated for their abilities to suppress the proliferation of human cancer cells associated with the digestion system and to inhibit the activity of two enzymes, α-glucosidase and pancreatic lipase. A pronounced anti-proliferative activity against the colorectal adenocarcinoma (HT-29) cells exhibited T. erecta extract (IC 50 = 1.5 mg/ml), while A. leptopus was most active against the gastric adenocarcinoma (AGS) (IC 50 = 0.2 mg/ml) and bladder cancer cells (BL-13) (IC 50 = 0.9 mg/ml). T. erecta extract was identified as an efficient inhibitor of α-glucosidase enzyme (IC 50 = 0.06 mg/ml). T. erecta, C. sulphureus and B. glabra extracts equally inhibited the activity of pancreatic lipase (IC 50 : 4.82 and 4.60 mg/ml, respectively). The results obtained in this study for the first time identified a number of potential health-enhancing properties of aqueous extracts obtained from edible flowers consumed by the indigenous people of Thailand.

We surveyed the extensive literature regarding the development, therapy and prevention of catheter-associated urinary tract infections (UTIs). We systematically searched for meta-analyses of randomised controlled trials available in Medline giving preference to the Cochrane Central Register of Controlled Trials and also considered other relevant publications, rating them on the basis of their quality. The studies' recommendations, rated according to a modification of the US Department of Health and Human Services (1992), give a close-to-evidencebased guideline for all medical disciplines, with special emphasis on urology where catheter care is an important issue. The survey found that the urinary tract is the commonest source of nosocomial infection, particularly when the bladder is catheterised (IIa). Most catheter-associated UTIs are derived from the patient's own colonic flora (IIb) and the catheter predisposes to UTI in several ways. The most important risk factor for the development of catheter-associated bacteriuria is the duration of catheterisation (IIa). Most episodes of short-term catheter-associated bacteriuria are asymptomatic and are caused by a single organism (IIa). Further organisms tend to be acquired by patients catheterised for more than 30 days. The clinician should be aware of two priorities: the catheter system should remain closed and the duration of catheterisation should be minimal (A). While the catheter is in place, systemic antimicrobial treatment of asymptomatic catheter-associated bacteriuria is not recommended (A), except for some special cases. Routine urine culture in an asymptomatic catheterised patient is also not recommended (C) because treatment is in general not necessary. Antibiotic treatment is recommended only for symptomatic infection (B). Long-term antibiotic suppressive therapy is not effective (A). Antibiotic irrigation of the catheter and bladder is of no advantage (A). Routine urine cultures are not recommended if the catheter is draining properly (C). A minority of patients can be managed with the use of the non-return (flip) valve catheter, avoiding the closed drainage bag. Such patients may exchange the convenience of on-demand drainage with an increased risk of infection. Patients with urethral catheters in place for 10 years or more should be screened annually for bladder cancer (C). Clinicians should always consider alternatives to indwelling urethral catheters that are less prone to causing symptomatic infection. In appropriate patients, suprapubic catheters, condom drainage systems and intermittent catheterisation are each preferable to indwelling urethral catheterisation (B). ଝ These guidelines based on the guidelines last published in 2006 by the European Association of Urology (ISBN-13:978-90-70244-59-0 ) were updated in cooperation with

e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 1 4 1 -1 4 7 a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Abstract Objective: Magainin II belongs to a family of antimicrobial peptides and has been shown to exhibit antibiotic activity in a wide range of organisms. Recent studies have also reported a significant antitumor effect of magainin II against various cancer cell lines and tumor mice models. In this study, we evaluated the cytotoxic and antiproliferative potency of magainin II in bladder tumor cells and normal fibroblasts. Methods: The antiproliferative and cytotoxic effect of magainin II was quantified by colorimetric WST-1-, bromodeoxyuridine (BrdU)-, and lactic dehydrogenase (LDH) assays in three bladder cancer cell lines (RT4, 647V, and 486P) and in the murine fibroblast cell line 3T3 as well as in a primary culture from human fibroblasts. The median inhibitory concentration (IC 50 ) values were determined for each assay, representing the concentration at which cell viability was reduced by 50%. Scanning electron microscopy (SEM) was used to visualize the morphologic effects of magainin II on bladder tumor cells and fibroblasts. Results: Magainin II inhibited cell proliferation of bladder cancer cells in a dosedependent manner. The average IC 50 of magainin II against all bladder cancer cell lines was 198.1 mM (range, 52.4-484.03 mM) for the WST-1 assay and 75.2 mM (range, 31.0-135.3 mM) for the BrdU assay. The normal murine and human fibroblast cell lines were not affected by magainin II and their IC 50 could not be determined at the concentrations of magainin II tested. LDH release was increased in all bladder tumor cell lines in the presence of magainin II, whereas normal fibroblasts showed no cell lysis. SEM demonstrated lethal membrane perforation by peptide pore formation in bladder cancer cells, but not in fibroblasts. Conclusion: Magainin II peptide exerts cytotoxic and antiproliferative efficacy by pore formation in bladder cancer cells but has no effect on normal murine or human fibroblasts. Magainin II may offer a novel therapeutic strategy in the treatment of bladder cancer with potentially low cytotoxic effects on normal cells.

To assess, in a systematic review and meta-analysis, the relative effectiveness of intravesical mitomycin C and bacillus Calmette-Guérin (BCG) for tumour recurrence, disease progression and overall survival in patients with medium-to high-risk Ta and T1 bladder cancer.

Objectives. To evaluate the outcomes of patients with muscle-invasive Stage T2-4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation. Methods. A total of 190 patients were treated on institutional prospective protocols using concurrent cisplatincontaining chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor. Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy, with the initial tumor response guiding subsequent therapy. One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received boost chemoradiation to 64 to 65 Gy. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors. The median follow-up was 6.7 years for all surviving patients. Results. The 5 and 10-year actuarial overall survival rate was 54% and 36%, respectively (Stage T2, 62% and 41%; Stage T3-T4a, 47% and 31%, respectively). The 5 and 10-year disease-specific survival rate was 63% and 59% (Stage T2, 74% and 66%; Stage T3-T4a, 53% and 52%), respectively. The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46% and 45% (Stage T2, 57% and 50%; Stage T3-T4a, 35% and 34%), respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity. Conclusions. The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage. One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders. UROLOGY 60: 62-68, 2002.

Introduction: The follow-up of patients with urothelial cell carcinoma (UCC) of the bladder is done by cystoscopy and, in most cases, cytology. The last decade, many urine-based tests for UCC have been developed and tested in different populations. For the urological practice, considering the amount of follow-up cystoscopies, especially urine markers for recurrent disease would be useful. Therefore, we reviewed the literature on these markers for recurrent UCC and compared our findings with recent review-articles. Methods: We performed a PubMed search. In case of primary and recurrent disease, the study was included if the patients under surveillance were reported separately. Patients with no evidence of disease at surveillance cystoscopy were considered to determine specificity. A marker was included if at least 2 studies from 2 different institutions/ authors were available. Results: The literature review yielded 64 articles. We found 18 markers (BTAstat, BTAtrak, NMP22, FDP, ImmunoCyt, Cytometry, Quanticyt, Hb-dipstick, LewisX, FISH, Telomerase, Microsatellite, CYFRA21-1, UBC, Cytokeratin20, BTA, TPS, Cytology) that met our criteria. BTAstat, NMP22, ImmunoCyt and cytology were evaluated in more than 750 patients. Telomerase, Cytokeratin20 and Hb-dipstick were tested in less than 250 patients. The highest median sensitivities were reported for CYFRA21-1 (85%), Cytokeratin20 (85%) and Microsatellite analysis (82%). The highest specificities were reported for Cytology (94%), BTA (92%) and Microsatellite analysis (89%). In comparison with recent reviews, median sensitivity was !5% lower for the surveillance group in 13/18 urine-based tests while specificity remained relatively constant between different patient groups. Conclusions: To our knowledge, this is the first review that assesses sensitivity and specificity of urine markers solely for UCC surveillance. In our view, Microsatellite analysis, ImmunoCyt, NMP22, CYFRA21-1, LewisX and FISH are the most promising markers for surveillance at this time. Nevertheless, clinical evidence is insufficient to warrant the substitution of the cystoscopic follow-up scheme by any of the currently available urine marker tests. Future studies may test some of the most sensitive and specific assays to reduce the cystoscopy frequency. However, our results show that initiators of these studies should anticipate a lower sensitivity than reported in the current literature. #

Purpose: Partial cystectomy is a bladder sparing procedure that has been used to treat invasive bladder cancer in highly selected patients. This study analyzes the outcomes of partial cystectomy in a contemporary cohort of patients to identify appropriate selection criteria for the procedure.

The role of the immune system in controlling the growth of tumour cells is highly complex and has been extensively debated. It is well documented that the immune system controls virally induced cancers, and there is evidence for a role of specific immunity in other types of tumours. The greater understanding of the regulation and optimization of adoptive, specific immune responses, and the better characterization of tumour-associated antigens indicate the way for active specific vaccination and cell therapy in urological tumours. Currently, bacille Calmette Guerin immunotherapy is established for localized bladder cancer and many experimental immunotherapies are under evaluation. Here we review some timely aspects of tumour immunology, and describe the current status and development of immunotherapy in prostate and bladder cancer.

diseases in an attempt to reduce or delay both recurrence and progression. Intermediate risk SBC is initially managed with prophylactic intravesical chemotherapy, whereas BCG immunotherapy has become the standard treatment for high-risk SBC, including T1G3, CIS and some recurrent Ta diseases. Significant limitations in efficacy and tolerability for the most widely used intravesical agents across all risk categories of SBC have favoured the search for new treatment alternatives. The present overview will address the rationale and the initial results of intravesical gemcitabine as a novel chemotherapeutic agent for SBC.

Objectives: Laparoscopic surgery is expanding among urologists as a minimally invasive treatment and may now be applied to treat neoplasms of the pelvic organs. Laparoscopic cystoprostatectomy has still not been well codified and illustrated. We describe a technique of laparoscopic radical cystoprostatectomy that we have developed in 10 patients after practicing in laparoscopic radical prostatectomy. Methods: Between June 2001 and July 2002, 10 men with bladder cancer underwent laparoscopic cystoprostatectomy with urinary diversion. This report details step by step our 5-port transperitoneal technique with primary access to the seminal vesicles and Denonvillier's fascia, ureters detection after umbilical arteries incision, endopelvic fascia incision and dorsal vein complex control before division of the vesical and prostatic fibrovascular pedicles with a harmonic scalpel. Results: We performed 6 orthotopic ileal neobladders, 2 sigmoid ureterostomies and 2 cutaneous ureterostomies. In all cases no conversion to open surgery was necessary. The mean time to perform the laparoscopic radical cystoprostatectomy, including the lymph node dissection, was 166 minutes (range 150-180). Mean estimated blood loss was 310 ml (range 220-440). Mean hospital stay was 8.1 days (range 7-9) for ileal orthotopic neobladder, 8 days (range 7-9) for sigmoid ureterostomy and 5 days for cutaneous ureterostomy. The mean follow up is 12.3 months (range 5-18). Two patients respectively with stage T2bN0 G2-3 and stage pT1N0 (plus carcinoma in situ) G3 transitional cell carcinoma and surgical margins tumor free had diffusive metastatic disease after 6 months. The other 8 patients are free from disease. Conclusions: Laparoscopic radical cystectomy is still an operation for pioneers but this procedure may be not strictly relegated to a few academic centers. In our opinion laparoscopic cystoprostatectomy is a feasible, fast, safe and easy procedure and urinary diversion may be performed with a laparoscopic, open or combined approach without reducing the advantages of laparoscopy. #

The histologic classification of bladder tumors remains an important predictor of treatment response and patient outcome, with pure nonurothelial tumors associated with poorer outcome compared with pure urothelial carcinoma (UC). Little, however, is known about the significance of UC with divergent (mixed) histologic features at transurethral resection of bladder tumor (TURBT). This study examined the incidence, pathologic spectrum, and clinical significance of this phenomenon.

Objectives To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille Calmette-Gue´rin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity.Patients and methods Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weekly×six and thereafter fortnightly×six) either with the standard or RD instillation.Results All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (sd) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose.Conclusion Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with high-risk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediate-risk lesions and for maintenance schedules.

Purpose: Presently there is a lack of effective, noninvasive tests for the detection and monitoring of bladder cancer. Measurement of fibridfibrinogen degradation products in urine has been shown to be a useful indicator of bladder carcinoma. The objective of this s t u d y w a s t o e v a l u a t e the AuraTek FDP" rapid immunoassay device for the detection of urinary fibrid fibrinogen degradation products associated with bladder cancer.

Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) wa...

www.gimle.fsm.it To investigate the relationship between exposure to polycyclic aromatic hydrocarbons (PAHs) and mortality for specific cancer sites, 1152 men, employed for at least 1 year at a prebake aluminium smelter, were followed-up from 1972 until 31 December 2001. Exposure to PAHs was estimated from a detailed reconstruction of the working history experienced in the plant by each cohort member

Purpose: To assess the potential reduction of small bowel volume receiving high-dose radiation by using kilovoltage X-ray cone beam computed tomography (CBCT) and quantized margin selection for adaptive bladder cancer treatment. Methods and Materials: Twenty bladder patients were planned conformally using a four-field, 15-mm uniform margin technique. Two additional planning target volumes (PTVs) were created using margins quantized to 5 and 10 mm in the superior direction only. CBCTs (ϳ8 scans/patient) were acquired during treatment. CBCT volumes were registered with CT planning scans to determine setup errors and to select the appropriate PTV of the day. Margin reduction in other directions was considered. Outlining of small bowel in every fraction is required to properly quantify the volume of small bowel spared from high doses. In the case of CBCT this is not always possible owing to artifacts created by small bowel movement and the presence of gas. A simpler method was adopted by considering the volume difference between PTVs created using uniform and adapted margins, which corresponds to the potential volume of small bowel sparing. Results: The average small bowel volume that can be spared by this form of adaptive radiotherapy is 31 ؎ 23 cm 3 (؎1 SD). The bladder for 1 patient was systematically smaller than the planning scan and hence demonstrated the largest average reduction of 76 cm 3 . The clinical target volume to PTV margins in other directions can be safely reduced to 10 mm except in the anterior direction where, like the superior direction, the bladder showed significant variation. Conclusions: Online CBCT-assisted plan selection based on quantized margins can significantly reduce the volume of small bowel receiving high doses for some bladder patients. CBCT allows the 15-mm margins used in some directions to be safely reduced to 10 mm.

Objective: The purpose of the present study was to evaluate the length of telomeres in patients with bladder cancer using a quantitative flow cytometry (flow-FISH) technique. Methods: Bladder washing samples from 51 patients with bladder cancer were obtained immediately before transurethral resection. The average length of telomere repeats was measured by flow-FISH, as previously reported. Results were expressed in molecular equivalents of soluble fluorochrome (MESF) units. Results: Bladder washing specimens provided adequate cell numbers for flow-FISH in 49 cases. The TEL means were 1014.71, 2343.36, 5567 and 18267.57 for Ta, T1, T2 and T3/4 tumors, respectively. Regarding grade it was obtained a mean MESF value of 1379.46, 3391.29 and 15925.11 for G1, G2 and G3, respectively. ANOVA demonstrated statistically significant differences in stage (p: 0.014) and tumor grades (p: 0.012). In relation to ploidy, we found a mean MESF value of 2701.37 and 16085.44 MESF units for diploid and aneuploid cells, respectively. Significant difference (p: 0.003) was observed between both groups. Conclusion: To date, this is the first report wherein telomere length was measured using flow-FISH method in exfoliated cells in urine from patients with bladder cancer. Further investigations are required to demonstrate whether flow-FISH technique might be considered as a tumor marker of bladder cancer. #

Schistosoma haematobium infection is strongly associated with urinary bladder cancer. Although numerous explanations have been proposed for this association, the nature of this relationship remains unresolved. This paper explores the hypothesis that inflammation and elevated cell proliferation play a major role in the development of bladder cancer in infected patients, possibly by increasing the level of genetic instability in the urothelium. The paper details in vivo and in vitro studies being done in our laboratories to test this hypothesis. These studies include population studies in which chromosomal breakage in the bladder of infected individuals is assayed using the micronucleus (MN) test on exfoliated urothelial cells. The approach also includes parallel studies in Vancouver with patients with long-term catheter drainage, a population with many similarities to schistosomiasis patients. In the in vitro studies we are co-incubating bladder cells with activated neutrophils or experimental conditions simulating inflammation. These studies show that inflammatory cells when activated can induce micronuclei in bladder cells and that this response is associated with loci on chromosome 11, a chromosome commonly altered during bladder carcinogenesis. A final approach being used is to assay chromosomal change (MN frequencies and numerical chromosome alterations) and level of proliferation (expression of proliferating cell nuclear antigen) in archival biopsies from schistosomiasis patients. Preliminary results show that a dysregulation of cell proliferation is occurring * Corresponding author, Tel. 604 291 4064; Fax 604 291 3040. 0027-5107/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0027-5107(93)E0198-Y 284 M.P. Rosin et al. / Mutation Research 305 (1994) [283][284][285][286][287][288][289][290][291][292] during cystitis in these patients. The extent to which this alteration affects the level of chromosomal breakage is yet to be determined.

The primary risk factor for bladder cancer is cigarette smoking. Using a combined analysis of 11 case-control studies, we have accurately measured the relationship between cigarette smoking and bladder cancer in men. Available smoking information on 2,600 male bladder cancer cases and 5,524 male controls included duration of smoking habit, number of cigarettes smoked per day and time since cessation of smoking habit for ex-smokers. There was a linear increasing risk of bladder cancer with increasing duration of smoking, ranging from an odds ratio (OR) of 1.96 after 20 years of smoking (95% confidence interval [CI] 1.48 -2.61) to 5.57 after 60 years (CI 4.18 -7.44). A dose relationship was observed between number of cigarettes smoked per day and bladder cancer up to a threshold limit of 15-20 cigarettes per day, OR ‫؍‬ 4.50 (CI 3.81-5.33), after which no increased risk was observed. An immediate decrease in risk of bladder cancer was observed for those who gave up smoking. This decrease was over 30% after 1-4 years, OR ‫؍‬ 0.65 (0.53-0.79), and was over 60% after 25 years of cessation, OR ‫؍‬ 0.37 (0.30 -0.45). However, even after 25 years, the decrease in risk did not reach the level of the never-smokers, OR ‫؍‬ 0.20. (0.17-0.24). The proportion of bladder cancer cases attributable to ever-smoking was 0.66 (0.61-0.70) for all men and 0.73 (0.66 -0.79) for men younger than 60. These estimates are higher than previously calculated. Int.

Keyhole limpet hemocyanin (KLH), the large respiratory glycoprotein from the primitive gastropod mollusc, Megathura crenulata, is a potent immunogen used classically as a carrier protein for haptens and more recently in human vaccines and for immunotherapy of bladder cancer. Two KLH isoforms were identified and isolated by high-performance anion exchange chromatography. Subsequent analyses disclosed that these isoforms--designated KLH-A and KLH-B--were composed of distinct subunits that differed in primary structure, molecular weight (KLH-A was 449,000 and KLH-B was 392,000), polymerization/reassociation characteristics, and O2-binding constants (KLH-A had a Ps0 of 7.32 and KLH-B had a Ps0 of 2.46). Both subunits appear to be composed of eight oxygen binding domains, and reassociate in solution only with like subunits. These results support the concept that structural and functional heterogeneity is a common feature of molluscan hemocyanins, and provide a rational basis for studying and optimizing the immunostimulatory properties of KLH. COMe BIOCHEM eHYSIOL l13B, 537-548, 1996. Proteins were digested with endoproteinase Lys-C (Boehringer Mannheim) at an enzyme/substrate ratio of 1 : 100 (w/w) for 18 h at 37°C in 25 mM Tris-HCl buffer (pH 8.9) plus 5 mM EDTA and 5% (v/v) acetonitrile. The digests were analyzed on a Vydac C4 column (9.4 x 250 mm). A 0.1% trifluoro-