New insights on occupational exposure and bladder cancer risk: a pooled analysis of two Italian case-control studies.

PURPOSE: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade. METHODS: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure. RESULTS: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only. CONCLUSIONS: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health.

H2AX phosphorylation level in peripheral blood mononuclear cells as an event-free survival predictor for bladder cancer.

Bladder cancer (BC) has a typical aetiology characterized by a multistep carcinogenesis due to environmental exposures, genetic susceptibility, and their interaction. Several lines of evidence suggest that DNA repair plays a role in the development and progression of BC. In particular, the study of individual susceptibility to DNA double strand breaks (DSBs) may provide valuable information on BC risk, and help to identify those patients at high-risk of either recurrence or progression of the disease, possibly personalizing both surveillance and treatment. Among the different DSB markers, the most well characterized is phosphorylation of the histone H2AX (γ-H2AX). We assessed any potential role of γ-H2AX as a molecular biomarker in a case-control study (146 cases and 146 controls) to identify individuals with increased BC risk and at high-risk of disease recurrence or progression. We investigated γ-H2AX levels in peripheral blood mononuclear cells before and after their exposure to ionizing radiation (IR). We did not find any significant difference among cases and controls. However, we observed a significant association between γ-H2AX basal levels and risk of disease recurrence or progression. In particular, both BC patients as a whole and the subgroup of non-muscle invasive BC (NMIBC) with high basal H2AX phosphorylation levels had a decreased risk of recurrence or progression (for all BC HR 0.70, 95%CI 0.52-0.94, P = 0.02; for NMIBC HR 0.68, 95%CI 0.50-0.92, P = 0.01), suggesting a protective effect of basal DSB signaling. Our data suggest that γ-H2AX can be considered as a potential molecular biomarker to identify patients with a higher risk of BC recurrence. © 2015 Wiley Periodicals, Inc.

Prognostic factors of 'high-grade' Ta bladder cancers according to the WHO 2004 classification: are these equivalent to 'high-risk' non-muscle-invasive bladder cancer?

OBJECTIVE: To determine the impact of prognostic factors of a series of high-grade Ta non-muscle-invasive bladder cancers (NMIBCs) according to the new International Society of Urological Pathology (ISUP) 1998/WHO 2004 grading system (previously classified as either TaG2 or TaG3). METHODS: One hundred and thirty-one high-grade Ta (105 G2 and 26 G3) cases were identified after independent review by two pathologists. Univariable and multivariable Cox regression models addressed recurrence and progression-free survival. Progression was defined as appearance of any T ≥1 recurrence after complete TUR (type 1) or occurrence of T ≥2 (type 2). RESULTS: Ten-year recurrence, type-1 and type-2 progression-free survival were 60, 75 and 95%, respectively. The previous grading system (G3 vs. G2) significantly predicted type 1 progression in the univariate model only. In the multivariate model, Ki67 was the only independent predictor of progression according to both definitions (HR = 5.25, p = 0.002 and HR = 6.16, p = 0.03, respectively). CONCLUSIONS: High-grade Ta NMIBC as defined by the WHO 2004 grading system cannot be equated with high-risk NMIBC. The risk of progression to muscle-invasive disease (type 2) is low, more in keeping with an intermediate-risk category of NMIBC. The previous WHO 1973 subcategorization into G2 and G3 is of little help in the prediction of outcome. Ki67 is a strong independent predictor of progression worthy of consideration for a clinical setting.

Polymorphisms in the XRCC1 gene modify survival of bladder cancer patients treated with chemotherapy.

Survival of bladder cancer patients depends on several factors including disease stage and grade at diagnosis, age, health status of the patient and the applied treatment. Several studies investigated the role of DNA repair genetic variants in cancer susceptibility, but only few studies investigated their role in survival and response to chemotherapy for bladder cancer. We genotyped 28 single nucleotide polymorphisms (SNP) in DNA repair genes in 456 bladder cancer patients, reconstructed haplotypes and calculated a score for combinations of the SNPs. We estimated Hazard Ratios (adjHR) for time to death. Among patients treated with chemotherapy, variant alleles of five SNPs in the XRCC1 gene conferred better survival (rs915927 adjHR 0.55 (95%CI 0.32-0.94); rs76507 adjHR 0.48 (95%CI 0.27-0.84); rs2854501 adjHR 0.25 (95%CI 0.12-0.52); rs2854509 adjHR 0.21 (95%CI 0.09-0.46); rs3213255 adjHR 0.46 (95%CI 0.26-0.80). In this group of patients, an increasing number of variant alleles in a XRCC1 gene score were associated with a better survival (26% decrease of risk of death for each additional variant allele in XRCC1). By functional analyses we demonstrated that the previous XRCC1 SNPs confer lower DNA repair capacity. This may support the hypothesis that survival in these patients may be modulated by the different DNA repair capacity determined by genetic variants. Chemotherapy treated cancer patients bearing an increasing number of "risky" alleles in XRCC1 gene had a better survival, suggesting that a proficient DNA repair may result in resistance to therapy and shorter survival. This finding may have clinical implications for the choice of therapy.

Prostate-specific antigen kinetics after I125-brachytherapy for prostate adenocarcinoma.

PURPOSE: To investigate a potential correlation between the achievement of a cut-off of nadir PSA (nPSA) after brachytherapy (BRT) with biochemical Disease-Free Survival (bDFS) and to define the rate of post-BRT PSA bounces. METHODS: Retrospective analysis was carried out in 105 consecutive patients affected with early-stage prostate adenocarcinoma who underwent (125)I BRT. Only patients with a minimum follow-up ≥24 months were included. Biochemical DFS was chosen as primary endpoint. RESULTS: At a median follow-up of 51.2 months, 3- and 5-year bDFS were 96.8 and 91.2%, respectively. Median time to biochemical failure (BF) was 54 months. By Kaplan-Meier analysis, patients achieving nPSA ≤ 0.35 ng/mL had significantly higher bDFS (3- and 5-year bDFS: 100 and 98.5 % vs. 83.3 and 66.7 %, respectively; p = 0.001). Bounce PSA occurred in 28.6% of patients, at a median time of 21.5 months. No BFs were observed in the bounce group. Achieving a nPSA ≤ 0.35 ng/mL was the only factor independently associated with long-term bDFS on both univariate (p = 0.000) and multivariate analysis (HR 3.82; p = 0.003). CONCLUSIONS: Patients attaining a nPSA ≤ 0.35 ng/mL are significantly more likely to experience long-term freedom-from-biochemical failure. Bounce PSA occurs in approximately 30% of patients. Time to onset of PSA increase seems the most reliable feature to distinguish bounce from failure. Tailored follow-up strategies are needed for patients at higher risk of recurrence, and caution is advised in interpreting an early increase in PSA levels in the first 24-30 months after BRT.

Prognostic factors including Ki-67 and p53 in Bacillus Calmette-Guérin-treated non-muscle-invasive bladder cancer: a prospective study.

OBJECTIVES: To prospectively evaluate the prognostic utility of the traditional prognostic factors and molecular markers p53 and Ki-67 in a homogeneous series of patients with non-muscle-invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: 192 intermediate- and high-risk NMIBC cases were enrolled. The variables in study were age, stage, grade, focality, tumour size, presence of associated carcinoma in situ, recurrence rate before BCG, maintenance for BCG, Ki-67 and p53. The endpoints considered were recurrence-free survival, progression-free survival, cancer-specific survival (CSS) and overall survival (OS). RESULTS: T stage resulted in being associated with CSS, whereas age with OS. BCG maintenance was a significantly favourable independent predictor of OS, CSS, recurrence and progression. In univariate analysis, the labelling index of Ki-67 was significantly associated with OS, CSS and progression. Multivariate analysis, however, confirmed this association only for OS. On the contrary, the labelling index of p53 was a significant predictor of recurrence, both in uni- and multivariate analyses, but with a HR inferior to 1. CONCLUSIONS: Ki-67 was an independent predictor of survival. p53 overexpression showed a significant yet inverse correlation with recurrence, thus showing little clinical utility. Age, stage and maintenance were confirmed as independent predictors of BCG response.

Myxoid renal tumor with myoepithelial differentiation mimicking a salivary gland pleomorphic adenoma: description of a case.

We herein report an unusual case of a low-grade myxoid renal epithelial neoplasm, with peculiar and previously unreported morphologic and immunohistochemical features. The lesion was characterized by noninfiltrative borders, myxoid stroma and elongated tubular and cordlike epithelial structures. These were lined by 2 different epithelial cell types, flat and elongated basal cells and cuboidal to spindle shaped eosinophilic luminal cells, with low-grade nuclear features and a few small nucleoli. The lesion morphologically resembled a pleomorphic adenoma of the salivary gland. The immunohistochemical profile interestingly confirmed the myoepithelial differentiation of the basal epithelial layer, as demonstrated by the coexpression of several myoepithelial markers such as p63, caldesmon, calponin, smooth muscle actin, and S-100, together with epithelial markers such as low and high-molecular weight cytokeratins. The tumor proved benign at follow-up. A definitive classification and histogenetic interpretation of this previously unreported tumor type awaits description of further cases showing similar features which, perhaps, as it may happen, went so far unnoticed.

Comparison between two commercially available chromogranin A assays in detecting neuroendocrine differentiation in prostate cancer and benign prostate hyperplasia.

BACKGROUND: Chromogranin A (CgA) is the neuroendocrine (NE) marker most frequently employed in detecting NE differentiation in prostate cancer patients, either at the tissue level or in the general circulation. METHODS: We compared the two commercially CgA assay kits in detecting NE differentiation, in benign hyperplasia (BPH) or prostate cancer (PC) patients (pts). 170 pts with BPH, 107 with BPH+inflammation, and 136 PC pts entered the study. CgA was measured in each patient with the immunoradiometric assay (IRMA) and with the enzyme-linked immunoabsorbent assay (ELISA). RESULTS: A moderate relationship was found between CgA measured with IRMA and ELISA in the whole population (Spearman's R=0.65, p<0.05), in BPH pts (R=0.76, p<0.05), in BPH+inflammation pts (R=0.53, p<0.05) and in PC pts (R=0.60, p<0.05). Twenty-two out of 62 pts (35.4%) with elevated ELISA CgA did not have increased IRMA CgA; by contrast, 21/61 pts (34.4%) with elevated IRMA CgA were not recognized as abnormal by the ELISA kit. CONCLUSIONS: CgA measured by the two assays provided a significant discordance rate, suggesting that the two kits might elicit different information.

Polymorphisms/haplotypes in DNA repair genes and smoking: a bladder cancer case-control study.

Bladder cancer is associated with tobacco smoking and occupational exposure. The repair of DNA damage has a key role in protecting the genome from the insults of cancer-causing agents. We analyzed 13 polymorphisms in seven DNA repair genes belonging to different repair pathways [X-ray repair cross-complementing group 1 (XRCC1): 26304C>T, 26651A>G, 28152A>G; xeroderma pigmentosum-D (XPD): 23591A>G, 35931A>C; excision repair complementing defective in Chinese hamster, group 1 (ERCC1): 19007C>T; XRCC3: 4541T>C, 17893A>G, 18067C>T; proliferating cell nuclear antigen (PCNA): 6084G>C; ERCC4: 30028C>T, 30147A>G; and XRCC2-31479A>G] in 317 incident bladder cancer patients and 317 controls. After adjustment for age and smoking, the PCNA-6084C variant was significantly associated with an increased risk of bladder cancer [CC + CG versus GG, odds ratio (OR), 1.61; 95% confidence interval (95% CI), 1.00-2.61], as well as the XRCC1-26651G variant (GG+AG versus AA: OR, 1.73; 95% CI, 1.17-2.56). After stratifying by smoking habits, an elevated risk for carriers of the XRCC3-18067T allele was detected both in current (TT versus CC: OR, 2.65; 95% CI, 1.21-5.80; CT versus CC: OR, 1.96; 95% CI, 1.09-3.52) and never smokers (TT versus CC: OR, 4.34; 95% CI, 1.14-16.46; CT versus CC: OR, 2.02; 95% CI, 0.72-5.66), whereas an opposite and slightly weaker effect was associated to the XRCC3-17893G allele in current smokers (GG versus AA: OR, 0.30; 95%CI, 0.11-0.82; AG versus AA: OR, 0.73; 95% CI, 0.42-1.27). XRCC3,XRCC1, ERCC4, and XPD-ERCC1 haplotype frequencies were estimated by the maximum likelihood method. The XRCC3-TAT haplotype was associated with an enhanced risk in the current smokers group (OR, 1.62; 95% CI, 1.15-2.29), whereas a reduction of the risk in the overall sample was observed in the presence of the XRCC3-TAC (OR, 0.69; 95% CI, 0.50-0.97). A significant protective effect of the XPD-ERCC1-ACC haplotype was observed among never smokers (OR, 0.16; 95% CI, 0.03-0.81). Our results suggest that polymorphisms and/or haplotypes in XRCC3, XRCC1, and PCNA genes and spanning XPD-ERCC1 region may modulate bladder cancer risk and that some of these effects may preferentially affect current smokers.

Relationship between Prostatic Specific Antigen (PSA) and volume of the prostate in the Benign Prostatic Hyperplasia in the elderly.

Increase of the Prostatic Specific Antigen (PSA) is a non-invasive, sensitive and specific markers for prostatic diseases, including prostatic cancer. However, age-related Benign Prostatic Hyperplasia (BPH), as well as prostatitis, may at the same time alter PSA values. The aim of this study was to evaluate the relationship between ageing and PSA, and whether age-specific upper normal limits of PSA should be considered for elderly patients. We evaluated 569 consecutive subjects aged 60 years or more (mean age 74.2 years) who were free from malignant prostatic disease, without clinical evidence of prostatic phlogosis and who were not receiving PSA levels affecting drugs. All patients underwent Digital Rectal Examination (DRE) and Trans-Rectal Ultrasonography (TRU), with determination of the three prostatic diameters, the Maximum Adenoma Diameter (MAD) and calculation of the prostatic volume (PV) by the ellipsoid formula. PSA was determined in all patients before DRE and TRU, and the PSA free ratio was determined in those with total PSA values >4 ng/ml. The PSA density was calculated according to the formula PSA/PV. One hundred and seventy-nine subjects (31.6%) were found to have PSA values >4 ng/ml: among them, 26 (14.5%) had values exceeding 10 ng/ml. Age was slightly correlated with PV (P<0.05), but not with PSA values. On the contrary, PSA values were strongly related with PV and MAD (P<0.01 both). Mean PSA-free ratio was 16.3+/-6.0% and most of patients had values in the so-called 'grey zone' of discrimination between benignity and malignity. Elevated PSA levels are common in older subjects without evidence of prostatic malignancy; PSA values are poorly affected by age itself and strongly correlated with increasing PV. These results suggest the possibility to consider as indicative of benignity PSA values between 4 and 10 ng/ml, when these values are associated with relevant increase of PV and with PSA-free ratio greater than 10%.

Shorter leukocyte telomere length is independently associated with poor survival in patients with bladder cancer.

BACKGROUND: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival. METHODS: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years. RESULTS: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non-muscle-invasive tumor/high-grade and with non-muscle-invasive tumor/non-high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10(-2) and 0.8 ± 0.2, P = 3.6 × 10(-2)). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10(-4)). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7-9.1; P = 1.2 × 10(-3)). CONCLUSIONS: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade. IMPACT: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer.

125I brachytherapy for localized prostate cancer: a single institution experience.

AIMS AND BACKGROUND: To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with 125I permanent brachytherapy at the University of Turin. METHODS AND STUDY DESIGN: A retrospective analysis was carried out on 167 consecutive patients with early stage prostate adenocarcinoma who underwent 125I brachytherapy between January 2003 and December 2010. A minimum follow-up of ≥ 12 months was mandatory for inclusion. Biochemical disease-free survival (defined on the basis of the ASTRO definition and the ASTRO-Phoenix definition) was chosen as the primary end point. Secondary end points were gastrointestinal and genitourinary toxicity (acute and late, defined according to the RTOG scale). RESULTS: With a median follow-up of 42 months (range, 13.5-90.7), biochemical disease-free survival at 3 and 5 years was respectively 91.1% and 85.7%, according to the ASTRO definition and 94.5% and 85.1% according to ASTRO-Phoenix definition (for statistical purposes, only the ASTRO definition was used). Hormone treatment and nadir PSA (cutoff of 0.35 ng/ml) were the only factors affecting biochemical disease-free survival both on univariate (P = 0.02 and P = 0.001, respectively) and multivariate analysis (HR 0.024; P = 0.021 and HR 21.6; P = 0.006, respectively). Only 3.6% of patients experienced ≥ grade 3 acute urinary toxicity and 5% ≥ grade 3 late urinary toxicity. Prior transurethral prostate resection was the only independent predictor of grade 3 late urinary toxicity on multivariate analysis (HR 0.13; P = 0.009). CONCLUSIONS: This mono-institutional series confirmed that brachytherapy is an effective and safe treatment modality for localized prostate cancer, with acceptable short- and long-term morbidity rates.

ERCC1 haplotypes modify bladder cancer risk: a case-control study.

Bladder cancer risk is highly influenced by environmental and/or predisposing genetic factors. In the last decades growing evidence of the major role played by DNA repair systems in the developing of bladder cancer has been provided. To better investigate the involvement of DNA repair genes previously reported to be significantly associated with bladder cancer risk, we examined in a case-control study (456 cases and 376 hospital controls) 36 single nucleotide polymorphisms (SNPs) in 10 DNA repair genes, through a better gene coverage and a deep investigation of the haplotype role. A single SNP analysis showed a significantly increased risk given by XRCC1-rs915927 G allele (OR=1.55, CI 95% 1.02-2.37 for dominant model) and a protective effect of the rare alleles of 3 ERCC1 SNPs: rs967591 (OR=0.66, CI 95% 0.46-0.95), rs735482 (OR=0.62, CI 95% 0.42-0.90) and rs2336219 (OR=0.63, CI 95% 0.43-0.93). Haplotype analysis revealed that cases had a statistically significant excess of XRCC3-TAGT and ERCC1-GAT haplotypes, whereas ERCC1-AAC, MGMT-TA, XRCC1-TGCC and ERCC2-TGAA haplotypes were significantly underrepresented. Together with other published data on large case-control studies, our findings provide epidemiological evidence supporting a link between DNA repair gene variants and bladder cancer development, and suggest that the effects of high-order interactions should be taken into account as modulating factors affecting bladder cancer risk. A detailed characterization of DNA repair genetic variation is warranted and might ultimately help to identify multiple susceptibility variants that could be responsible for joint effects on the risk.

Intake of fruits and vegetables and polymorphisms in DNA repair genes in bladder cancer.

The objective is to investigate the relationships between fruit and vegetable intake, DNA repair gene polymorphisms and the risk of bladder cancer. We have analyzed a hospital-based case-control study of 266 individuals with incident, histologically confirmed bladder cancer diagnosed between 1994 and 2003. Controls (n = 193) were patients treated for benign diseases recruited daily in a random fashion from the same hospital as the cases. All cases and controls were interviewed face-to-face for major risk factors, along fruit and vegetable consumption. Odds ratios (ORs) for fruit and vegetable intake and DNA repair gene polymorphisms were adjusted for age and smoking status, using unconditional logistic regression. A statistically significant decreased risk was observed for fruit and vegetable intake above median (versus below the median) [unadjusted OR 0.61, confidence interval (CI) 95% 0.50-0.96 and OR 0.54, CI 95% 0.39-0.80, respectively]; the decreased risk persisted after adjustment for age and cigarette smoking (OR 0.73, CI 95% 0.49-1.01 and OR 0.86, CI 95% 0.56-1.08, respectively). The fruits and vegetables associated with decreased risks included leafy green vegetables, cruciferous vegetables, apples and citrus fruits. We did not find any interactions between DNA repair gene polymorphisms and fruit and vegetable intake. This study found a reduced risk associated with fruit and vegetable intake. No interaction was observed between fruit and vegetable consumption and DNA repair gene polymorphisms.

Immunohistochemical study of neuroendocrine differentiation in primary glandular lesions and tumors of the urinary bladder.

OBJECTIVE: Neuroendocrine (NE) cells are uncommon in primary adenocarcinoma (AC) and other glandular lesions of the bladder, with no recent study series concerning its significance in differential diagnosis, prognosis or biologic significance. STUDY DESIGN: Sixteen primary bladder AC (enteric-type [n = 71, mucinous [n = 6] and not otherwise specified [NOS] [n = 31), 4 cases of urothelial carcinoma with glandular differentiation, 20 cases of glandular cystitis and 3 urachal remnants with intestinal metaplasia constituted the study series. In addition, 20 specimens of normal-looking urothelium, 15 conventional urothelial carcinomas and 5 small cell carcinoma (SCC) cases were included for comparison. NE differentiation included detection of chromogranin A, neuron-specific enolase (NSE) and synaptophysin by immunohistochemistry. The statistical analysis included the chi2 or Fisher exact test. RESULTS: Chromogranin A-positive cells were present in 60% (11 of 16) of primary AC, all of enteric or mucinous type, but not in any of the 3 NOS-type AC investigated. NE differentiation in bladder AC subtypes resulted in highly significant differences between enteric or mucinous vs. NOS type (p = 0.0023). NE differentiation was also different in urachal vs. nonurachal AC (p = 0.020) and primary bladder AC vs. conventional invasive urothelial carcinoma (p < 0.001). Synaptophysin-positive cells were seen in 2 (12.5%) of the 16 primary AC cases, and NSE was negative in the 16 primary bladder AC. All urachal remnants and 70% of glandular cystitis examples had chromogranin A-immunoreactive cells. One of 4 urothelial carcinomas with glandular differentiation had chromogranin A-immunoreactive cells, but this was not significant when compared with primary AC (p = 0.1). Normal-looking bladder urothelium and conventional urothelial carcinoma specimens had no chromogranin A-immunoreactive cells. The 5 SCC cases investigated were positive for chromogranin A. No correlation was found between NE differentiation and outcome of primary bladder AC or urothelial carcinoma with glandular differentiation. CONCLUSION: Primary bladder AC, cystitis glandularis and urachal remnants with intestinal metaplasia showed variable degrees of NE differentiation, with no apparent clinical correlation or prognostic significance. However, the absence of NE differentiation in NOS-type primary bladder AC may help in better defining this uncommon subtype of primary bladder AC.

Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC).

OBJECTIVE: Phase I studies have so far demonstrated that intravesical Gemcitabine up to a 40 mg/ml concentration is well tolerated and has a substantial ablative activity on high-risk BCG refractory SBC. New treatment options are needed for intermediate-risk SBC recurring after conventional intravesical treatments. The purpose of the present study was to investigate the ablative efficacy of intravesical Gemcitabine on intermediate-risk SBC. METHODS: The study was designed as a two-stage phase II trial, with a sample size of 39 patients. The efficacy of intravesical Gemcitabine at a concentration of 40 mg/ml (2000 mg in 50 ml saline solution) administered weekly for 6 weeks was assessed on a single marker tumour left in the bladder after a complete TUR of all other lesions. Patients underwent TUR or biopsy at the site of the marker lesion 2 weeks after completion of the treatment. RESULTS: Complete response was observed in 22 out of 39 patients (56%). No progression was observed among the 17 non-responders. Neither systemic nor local side effects generally exceeded grade I toxicity. CONCLUSION: The ablative effect of Gemcitabine produced a higher number of responses than the minimum required by the protocol to indicate a significant probability of drug efficacy. It is worth testing the drug in phase III trials to assess for durability of response.

Determinants of 4-aminobiphenyl-DNA adducts in bladder cancer biopsies.

Exposure to 4-aminobiphenyl (4-ABP) is an important determinant of urinary bladder cancer in humans. We have analyzed by gas chromatography-mass spectrometry the DNA adducts of 4-ABP in 75 bladder cancer biopsies. The purpose was to understand whether smoking, N-acetyltransferase 2 (NAT2) polymorphism, diet or tumor grade were determinants of 4-ABP-DNA levels. 4-ABP-DNA adducts were above the detection limit of 0.1 fmol/microg DNA for 37/75 patients. Overall the level of adducts was 2.7 +/- 0.7 (mean +/- SE) fmol/microg DNA (86 +/- 22 adducts/10(8) normal nucleotides, mean +/- SE). A strong association with grade was observed. In the group of patients with detectable 4-ABP-DNA adducts the odds ratio for having a tumor grade of 2 or 3 was respectively 4.3 (95% CI 0.8-21.9) and 6 (1.3-27.5), compared with grade 1. A non-statistically significant association was found between adduct levels and the deduced slow acetylator phenotype in grades 2 and 3. The intake of fruit and vegetables produced a lower frequency of detectable adducts, though the association was not statistically significant. Detectable 4-ABP-DNA adducts were clearly associated with current smoking in higher tumor grades (grade 3 versus grades 1 + 2, odds ratios 10.4; 95% CI 1.7-63.1). Overall, our findings indicate that higher levels of DNA adducts characterize more invasive tumors (higher tumor grades). This seems to be facilitated by smoking and contrasted by the intake of fruit and vegetables.