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Nutrition may impact bladder cancer survival. We examined the association between diet quality and overall and bladder cancer-specific survival. Bladder cancer cases from a population-based study reported pre-diagnosis diet. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010). Vital status was ascertained from the National Death Index. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards and competing risks regression models. Overall AHEI-2010 adherence was not associated with overall or bladder cancer-specific survival among non-muscle invasive bladder cancer (NMIBC) cases (HR, 1.00; 95% CI, 0.98–1.01; HR, 1.00; 95% CI, 0.97–1.02) or muscle invasive bladder cancer (MIBC) cases (HR, 0.99; 95% CI, 0.96–1.03; HR, 1.01, 95% CI 0.97–1.06). AHEI-2010 sugar-sweetened beverages adherence was associated with poorer overall survival (HR, 1.04; 95% CI, 1.01–1.08) and AHEI-2010 sodium adherence was associated with better overall and bladder cancer-specific survival after NMIBC diagnosis (HR, 0.92, 95% CI, 0.85–1.00; HR, 0.82; 95% CI, 0.68–0.98). AHEI-2010 fruit adherence was associated with poorer overall and bladder cancer-specific survival after MIBC diagnosis (HR, 1.17; 95% CI, 1.02–1.33; HR, 1.26; 95% CI, 1.03–1.55). Consumption of sugar-sweetened beverages, sodium, and fruit, not overall AHEI-2010 adherence, may be associated with bladder cancer survival.

BACKGROUND: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage. OBJECTIVE: The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets. METHODS: Two independent cohorts of NMIBC patients were analyzed using a biomarker discovery and validation approach, respectively. RESULTS: miRNA Let-7f-5p showed the strongest association with recurrence across both cohorts. Let-7f-5p levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue. We assessed the therapeutic potential of targeting Lin28, a negative regulator of Let-7f-5p, with small-molecule inhibitor C1632. Lin28 inhibition significantly increased levels of Let-7f-5p expression and led to significant inhibition of viability and migration of HTB-2 cells. CONCLUSIONS: We have identified Let-7f-5p as a miRNA biomarker of recurrence in NMIBC tumors. We further demonstrate that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel potential therapeutic opportunity in NMIBC.

We examined the interaction between common genetic bladder cancer variants, diet quality, and bladder cancer risk in a population-based case-control study conducted in New England.At the time of enrollment, 806 bladder cancer cases and 974 controls provided a DNA sample and completed a diet history questionnaire. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010) score. Single nucleotide polymorphisms (SNPs) reported in genome-wide association studies to be associated with bladder cancer risk were combined into a polygenic risk score and also examined individually for interaction with the AHEI-2010. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.A 1-standard deviation increase in polygenic risk score was associated with higher bladder cancer risk (OR, 1.34; 95% CI 1.21-1.49). Adherence to the AHEI-2010 was not associated with bladder cancer risk (OR, 0.99; 95% CI 0.98-1.00) and the polygenic risk score did not appear to modify the association between the AHEI-2010 and bladder cancer risk. In single-SNP analyses, rs8102137 (bladder cancer risk allele, C) modified the association between the AHEI-2010 total score and bladder cancer risk, with the strongest evidence for the AHEI-2010 long chain fat guideline (OR for TT, 0.92; 95% CI 0.87-0.98; OR for CT, 1.02; 95% CI 0.96-1.08; OR for CC, 1.03; 95% CI 0.93-1.14; p for interaction, 0.02).In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk.

INTRODUCTION AND OBJECTIVE:50% to 75% of patients with non-muscle invasive bladder cancer (NMIBC) experience recurrences within 6 to 12 years of diagnosis, and the cost of screening makes bladder c...

Patients undergoing transthoracic needle core lung biopsy (TTNB) are at risk for biopsy-related pneumothorax. Instilling pleural sealant at the pleural puncture site reduces this risk. The impact of histologic changes associated with pleural sealant on assessing the histologic type and pathologic stage in lung cancer resection specimens has not been previously evaluated. All lung cancer resection specimens from 2015 to 2018 in which polyethylene glycol hydrogel pleural sealant was instilled during TTNB were reviewed. Thirty-three cases were identified. TTNB preceded lobectomy by an average of 35 days. Amphophilic, weakly polarizable, crinkled pleural sealant material was associated with tumor in 11 cases (33%), including 8 adenocarcinomas, 2 squamous cell carcinomas, and 1 pleomorphic carcinoma that averaged 1.7 cm in greatest dimension. Surrounding the sealant material was a 0.25 to 1.0 cm in greatest dimension pseudocystic space with a thin granulomatous rim of macrophages and multinucleated giant cells that occupied on average 17% of the tumoral area. Pleural sealant could have impaired assessment of pathologic stage in 1 case by obscuring the visceral pleural elastic layer, but definitive visceral pleural invasion was present nearby. Although hydrogel pleural sealant instilled during TTNB has the potential to obscure important histologic features, in practice, it appears to have little or no adverse impact on the assessment of histologic type and pathologic stage in subsequent lung cancer resection specimens. Recognition of the histologic appearance of hydrogel pleural sealant and its associated tissue response is important for avoiding diagnostic misinterpretation.

Prostate cancer (PCa) recurrences are often predicted by assessing the status of surgical margins (SM)– positive surgical margins (PSM) increase the chances of biochemical recurrence by 2-4 times which may lead to PCa recurrence. To this end, an electrical impedance acquisition system with a microendoscopic probe was employed in an ex-vivo study of human prostates. This system measures the tissue bioimpedance over a range of frequencies (1 kHz to 1MHz), and computes a number of Composite Impedance Metrics (CIM). A classifier trained using CIM data can be used to classify tissue as benign or cancerous. The system was used to collect the impedance spectra from 14 excised prostates, which were obtained from men undergoing radical prostatectomy, for a total of 23 cancerous and 53 benign measurements. The data revealed statistically significant (p < 0.05) differences in the impedance properties of the benign and tumorous tissues, and among the measurements taken on the apical, base, and lateral surface of the prostate. Further, in the leave-one-patient-out cross validation, a maximum predictive accuracy of 90.79% was achieved by combining high frequency CIM phase data to train a support vector machine classifier with a radial basis function kernel. The observations are consistent with the physiology and morphology of benign and malignant prostate tissue. CIMs were found to be an effective tool in distinguishing benign from cancerous tissues.

Background: The high rate of non-muscle–invasive bladder cancer recurrence is a major challenge in patient management. miRNAs functionally regulate tumor cell proliferation and invasion, and have strong potential as biomarkers because they are robust to degradation. The objective of this project was to identify reproducible prognostic miRNAs in resected non-muscle–invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype. Methods: We utilized patients diagnosed with primary non-muscle–invasive bladder cancer in three independent cohorts for a biomarker discovery/validation approach. Baseline tumor tissue from patients with the clinically challenging, non-muscle–invasive primary low stage (Ta), high grade, and T1 tumors (tumors extending into the lamina propria) comprised the discovery cohort (n = 38). We isolated the tumor tissue RNA and assessed a panel of approximately 800 miRNAs. Results: miR-26b-5p was the top-ranking prognostic tumor tissue miRNA, with a time-to-recurrence HR 0.043 for levels above versus below median, (Padj = 0.0003). miR-26b-5p was related to a dose-response reduction in tumor recurrence, and levels above the median were also associated with reduced time-to-progression (Padj = 0.02). We used two independent longitudinal cohorts that included both low-grade and high-grade Ta and T1 tumors for validation and found a consistent relationship between miR-26b-5p and recurrence and progression. Conclusions: Our results suggest that miR-26b-5p levels may be prognostic for non-muscle–invasive bladder cancer recurrence, and can feasibly be assessed in baseline tumor tissue from a wide variety of clinical settings. Impact: Early identification of those non-muscle–invasive bladder tumor patients with refractory phenotypes would enable individualized treatment and surveillance.

Radially configured microendoscopic electrical impedance probes intended for intraoperative surgical margin assessment during robot-assisted laparoscopic prostatectomy (RALP) were examined through simulation, bench-top experimentation, and ex vivo tissue studies. Three probe designs with 8, 9, and 17 electrodes, respectively, were analyzed through finite element method based simulations. One mm diameter spherical inclusions ( $\sigma _{\rm inclusion} =1~{\rm S}/{\rm m}$ ) are positioned at various locations within a hemispherical background ( $\sigma _{\rm background} =0.1~{\rm S}/{\rm m}$ ) of radius 5 mm. An 8-electrode configuration is not able to localize the inclusion at these positions while 9 and 17-electrode configurations are able to accurately reconstruct the inclusion at maximum depth of 1 mm and 3 mm, respectively. All three probe designs were constructed and evaluated using saline phantoms and ex vivo porcine and human prostate tissues. The 17-electrode probe performed best in saline phantom studies, accurately reconstructing high contrast, 1-mm-diameter metal cylindrical inclusions in a saline bath ( $\sigma _{\rm saline} =0.1~{\rm S}/{\rm m}$ ) with a position and area error of 0.46 mm and 0.84 ${\rm mm}^{2}$ , respectively. Additionally, the 17-electrode probe was able to adequately distinguish cancerous from benign tissues in three ex vivo human prostates. Simulations, bench-top saline experiments, and ex vivo tissue sampling suggest that for intraoperative surgical margin assessment during RALP, the 17-electrode probe (as compared to an 8 and 9 electrode probe) will be necessary to provide sufficient accuracy and sensitivity.

Bladder cancer is the fourth most common cancer among men in the United States and more than half of patients experience recurrences within 5 years after initial diagnosis. Additional clinically informative and actionable biomarkers of the recurrent bladder cancer phenotypes are needed to improve screening and molecular therapeutic approaches for recurrence prevention. MicroRNA-34a (miR-34a) is a short noncoding regulatory RNA with tumor suppressive attributes. We leveraged our unique, large, population-based prognostic study of bladder cancer in New Hampshire, United States to evaluate miR-34a expression levels in individual tumor cells to assess prognostic value. We collected detailed exposure and medical history data, as well as tumor tissue specimens from bladder patients and followed them long-term for recurrence, progression and survival. Fluorescence-based in situ hybridization assays were performed on urothelial carcinoma tissue specimens (n = 229). A larger proportion of the nonmuscle invasive tumors had high levels of miR-34a within the carcinoma cells compared to those tumors that were muscle invasive. Patients with high miR-34a levels in their baseline nonmuscle invasive tumors experienced lower risks of recurrence (adjusted hazard ratio 0.57, 95% confidence interval 0.34-0.93). Consistent with these observations, we demonstrated a functional tumor suppressive role for miR-34a in cultured urothelial cells, including reduced matrigel invasion and growth in soft agar. Our results highlight the need for further clinical studies of miR-34a as a guide for recurrence screening and as a possible candidate therapeutic target in the bladder.

Objective Currently no efficient and reliable technique exists to routinely assess surgical margins during a radical prostatectomy. Electrical impedance spectroscopy (EIS) has been reported as a potential technique to provide surgeons with real-time intraoperative margin assessment. In addition to providing a quantified measure of margin status, a co-registered electrical impedance tomography (EIT) image presented on a surgeon's workstation could add value to the margin assessment process. Approach To investigate this, we conducted a comparative study between EIS and EIT to evaluate the potential these technologies might have for margin assessment. EIS and EIT data was acquired from ex vivo human prostates using a multi-electrode endoscopic impedance acquisition probe. Main results EIS and EIT show good predictive performance with a 0.76 and 0.80 area-under-curve (AUC), respectively, when considering discrete frequencies only. A machine learning (ML) algorithm is implemented to combine features, which improves the AUCs of EIS and EIT to 0.84 and 0.85, respectively. Single-step EIT takes significantly less time to reconstruct than multi-step EIT, yet provides similarly accurate classification results, making the single-step approach a potential candidate for real-time margin assessment. While the ML-based approach clearly exhibits benefits as compared to the single feature assessment, the decision to use EIS versus EIT is unclear since each approach performs better for different subsets of tissue classifications. Significance The results presented in this paper corroborate our previous studies and present the strongest evidence yet that an intraoperative-capable impedance probe can be used to distinguish benign from malignant prostate tissues. An in vivo study with a large cohort will be necessary to definitively determine the preferred approach and to show the clinical effectiveness of using this technology for margin assessment.

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Introduction Dysregulation of the hedgehog signaling pathway has been linked to the development and progression of a variety of different human tumors including cancers of the skin, brain, colon, prostate, blood, and pancreas. We assessed the clinicopathological factors that are potentially related to expression of Gli1, the transcription factor that is thought to be the most reliable marker of hedgehog pathway activation in bladder cancer. Methods Bladder cancer cases were identified from the New Hampshire State Cancer Registry as histologically confirmed primary bladder cancer diagnosed between January 1, 2002, and July 31, 2004. Immunohistochemical analysis was performed on a tissue microarray to detect Gli1and p53 expression in these bladder tumors. We computed odds ratios (ORs) and their 95% CIs for Gli1 positivity for pathological category using T category (from TNM), invasiveness, and grade with both the World Health Organization 1973 and World Health Organization International Society of Urological Pathology criteria. We calculated hazard ratios and their 95% CI for Gli1 positivity and recurrence for both Ta-category and invasive bladder tumors (T1+). Results A total of 194 men and 67 women, whose tumors were assessable for Gli1 staining, were included in the study. No appreciable differences in Gli1 staining were noted by sex, age, smoking status, or high-risk occupation. Ta-category tumors were more likely to stain for Gli1 as compared with T1-category tumors (adjusted OR = 0.38, CI: 0.17–0.87). Similarly, low-grade (grades 1–2) tumors were more likely to stain for Gli1 as compared with high-grade tumors (grade 3) (adjusted OR = 0.44, CI: 0.21–0.93). In a Cox proportional hazards regression analysis, non–muscle-invasive bladder tumors expressing Gli1 were less likely to recur (adjusted hazard ratio = 0.48; CI: 0.28–0.82; P Conclusion Our findings indicate that Gli1 expression may be a marker of low-stage, low-grade bladder tumors and an indicator of a reduced risk of recurrence in this group.

Objective To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism), as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment. Patients and methods We analysed variant genotypes hypothesised to modify these processes in 563 patients with urothelial-cell carcinoma enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, USA. After diagnosis, patients were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data. Cox proportional hazards regression was used to assess the relationship between single nucleotide polymorphisms (SNPs) and prognosis endpoints. Results Patients with aldehyde dehydrogenase 2 (ALDH2) variants had a shorter time to first recurrence (adjusted non-invasive hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.29–2.78). There was longer survival among patients with non-invasive tumours associated with DNA repair X-ray repair cross-complementing protein 4 (XRCC4) heterozygous genotype compared with wild-type (adjusted HR 0.53, 95% CI 0.38–0.74). Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction < 0.001). Conclusions Our analysis suggests candidate prognostic SNPs that could guide personalised bladder cancer surveillance and treatment.

BACKGROUND In the Western world, bladder cancer is the fourth most common cancer in men and the eighth most common in women. Recurrences frequently occur, and continued surveillance is necessary to identify and treat recurrent tumors. Efforts to identify risk factors that are potentially modifiable to reduce the rate of recurrence are needed. METHODS Cigarette smoking behavior and body mass index were investigated at diagnosis for associations with bladder cancer recurrence in a population-based study of 726 patients with bladder cancer in New Hampshire, United States. Patients diagnosed with non–muscle invasive urothelial cell carcinoma were followed to ascertain long-term prognosis. Analysis of time to recurrence was performed using multivariate Cox regression models. RESULTS Smokers experienced shorter time to recurrence (continuing smoker hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 1.08-2.13). Although being overweight (body mass index > 24.9 kg/m2) at diagnosis was not a strong independent factor (HR = 1.33, 95% CI = 0.94-1.89), among continuing smokers, being overweight more than doubled the risk of recurrence compared to smokers of normal weight (HR = 2.67, 95% CI = 1.14-6.28). CONCLUSIONS These observational results suggest that adiposity is a risk factor for bladder cancer recurrence, particularly among tobacco users. Future intervention studies are warranted to evaluate whether both smoking cessation and weight reduction strategies reduce bladder tumor recurrences. Cancer 2014;120:408–414. © 2013 American Cancer Society.

A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multivariable linear regression (P = 6.46×10(-11); n = 278). The association pattern is similar in non-muscle-invasive tumors, stages Ta (P = 3.10×10(-5); n = 173) and T1 (P = 2.64×10(-5); n = 60), and muscle-invasive tumors, stages T2 (P =.01; n = 23) and T3/4 (P =.03; n = 22). The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. Future clinical studies will be needed to validate PSCA as a therapeutic target for bladder cancer.

Fenestral and stomatal diaphragms are endothelial subcellular structures of unknown function that form on organelles implicated in vascular permeability: fenestrae, transendothelial channels, and caveolae. PV1 protein is required for diaphragm formation in vitro. Here, we report that deletion of the PV1-encoding Plvap gene in mice results in the absence of diaphragms and decreased survival. Loss of diaphragms did not affect the fenestrae and transendothelial channels formation but disrupted the barrier function of fenestrated capillaries, causing a major leak of plasma proteins. This disruption results in early death of animals due to severe noninflammatory protein-losing enteropathy. Deletion of PV1 in endothelium, but not in the hematopoietic compartment, recapitulates the phenotype of global PV1 deletion, whereas endothelial reconstitution of PV1 rescues the phenotype. Taken together, these data provide genetic evidence for the critical role of the diaphragms in fenestrated capillaries in the maintenance of blood composition.

Diagnostic confirmation of cancer in solid organs is based on biopsy findings. In a standard 12-core prostate biopsy protocol, conventional biopsy needles sample only 0.95% (~0.228 cm3) of a typical 24-cm3 prostate gland. The primary objective of this study was to enhance the sensitivity of standard biopsy protocol by gauging electrical properties of tissue simultaneously with tissue extraction for histopathology analysis. A conventional biopsy (Bx) needle was instrumented with an electrical impedance spectroscopy (EIS) sensor to interrogate the tissue volume surrounding the needle tip. The EIS-Bx device was evaluated in a series of saline bath and ex vivo porcine experiments. It was found to sense a volume of 0.286 cm3 of tissue around the needle tip. EIS measurements were recorded from three ex vivo human prostates using the device, and the extracted biopsy cores were histologically assessed. Prostate conductivity σ ranged from 0.179 to 0.3310S/m for benign tissues and 0.0746 to 0.0837 S/m for malignant tissues at frequencies ranging from 1 to 100 kHz. Relative permittivity er ranged from 2.10 × 106 to 2.9 × 104 for benign and 6.63 × 105 to 5.3 × 103 for cancer tissues over the same frequency range. Both are found to be significantly higher in normal prostate tissues than in malignant tissue (p

Background: Evidence suggests that global methylation levels in blood cell DNA may be a biomarker for cancer risk. To date, most studies have used genomic DNA isolated from blood or urine as a surrogate marker of global DNA methylation levels in bladder tumor tissue. Methods: A subset of 50 bladder cancer cases was selected from the New England Bladder Cancer Case–Control Study. Genomic DNA was isolated from buffy coat, buccal cells, serum, and formalin-fixed, paraffin-embedded tissue for each participant. DNA methylation at four CpG sites within the long interspersed nucleotide element (LINE-1) repetitive element was quantified using pyrosequencing and expressed as a mean methylation level across sites. Results: Overall, the mean percent (%) LINE-1 5-methylcytosine (%5MeC) level was highest in serum (80.47% ± 1.44%) and lowest in bladder tumor DNA (61.36% ± 12.74%) and levels varied significantly across tissue types (P = 0.001). An inverse association between LINE-1 mean %5MeC and tumor stage (P = 0.001) and grade (P = 0.002) was observed. A moderate correlation between patient-matched serum and buffy coat DNA LINE-1 %5MeC levels was found (r = 0.32, P = 0.03) but levels were uncorrelated among other matched genomic DNA samples. Conclusions: The mean promoter LINE-1 %5MeC measurements were correlated between buffy coat and serum DNA samples. No correlation was observed between genomic DNA sources and tumor tissues; however a significant inverse association between tumor percent LINE-1 methylation and tumor stage/grade was found. Impact:LINE-1 methylation measured in case blood DNA did not reflect that observed in bladder tumor tissue but may represent other factors associated with carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(7); 1143–8. ©2012 AACR.

We investigate the distribution of bladder tumor category and stage in Northern New England by geographic region, smoking status, and over time. 1091 incident bladder cancer cases from the New England Bladder Cancer Study (NEBCS), a large population-based case-control study carried out in Maine, New Hampshire, and Vermont (2001–2004) and 680 bladder cancer cases from previous case-control studies in New Hampshire (1994–2000) were used in the analysis. Of 1091 incident bladder cancer cases from the NEBCS, 26.7% of tumors were papillary urothelial neoplasms of low malignant potential (PUNLMP), 26.8% low-grade papillary urothelial carcinomas (PUC-LG), 31.3% high-grade papillary urothelial carcinomas (PUC-HG), 9.1% nonpapillary urothelial carcinomas (non-PUC), and 4.3% carcinoma in situ (CIS). Approximately 70% of cases were noninvasive (Tis/Ta), and all PUNLMP cases were of the Ta category. By contrast, half of all PUC-HG carcinomas were invasive. Short-term time trend analysis within the NEBCS (2001–2004) indicated an increase in the percentage of PUNLMP (P-trend P-trend = 0.02) and for PUC-LG an increase in the percentage of non-invasive tumors (P-trend 0.04). Our findings suggest possible short-term trends with an increase in the percentage of PUNLMP and a change in the percentage of PUC-LG towards non-invasive disease.

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case-control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case-control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure.

Aromatic amine components in hair dyes and polymorphisms in genes that encode enzymes responsible for hair dye metabolism may be related to bladder cancer risk. We evaluated the association between hair dye use and bladder cancer risk and effect modification by N-acetyltransferase-1 (NAT1), NAT2, glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) genotypes in a population-based case-control study of 1193 incident cases and 1418 controls from Maine, Vermont and New Hampshire enrolled between 2001 and 2004. Individuals were interviewed in person using a computer-assisted personal interview to assess hair dye use and information on potential confounders and effect modifiers. No overall association between age at first use, year of first use, type of product, color, duration or number of applications of hair dyes and bladder cancer among women or men was apparent, but increased risks were observed in certain subgroups. Women who used permanent dyes and had a college degree, a marker of socioeconomic status, had an increased risk of bladder cancer [odds ratio (OR) = 3.3, 95% confidence interval (CI): 1.2-8.9]. Among these women, we found an increased risk of bladder cancer among exclusive users of permanent hair dyes who had NAT2 slow acetylation phenotype (OR = 7.3, 95% CI: 1.6-32.6) compared to never users of dye with NAT2 rapid/intermediate acetylation phenotype. Although we found no relation between hair dye use and bladder cancer risk in women overall, we detected evidence of associations and gene-environment interaction with permanent hair dye use; however, this was limited to educated women. These results need confirmation with larger numbers, requiring pooling data from multiple studies.

Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2) = 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis.

The association between secondhand smoke (SHS) exposure and bladder cancer is inconclusive. Epigenetic alterations in bladder tumors have been linked to primary cigarette smoking and could add to the biological plausibility of an association between SHS exposure and bladder cancer.SHS exposure is associated with DNA methylation in bladder tumors.Using an array-based approach, we profiled DNA methylation from never smoking cases of incident bladder cancer. Analyses examined associations between individual loci's methylation with SHS variables (exposure in adulthood, childhood, occupationally, and total exposure). A canonical pathway analysis was used to find pathways significantly associated with each SHS exposure type.There is a trend toward increased methylation of numerous CpG loci with increasing exposure to adulthood, occupational, and total SHS. Discrete associations between methylation extent of several CpG loci and SHS exposures demonstrated significantly increased methylation of these loci across all types of SHS exposure. CpGs with SHS-related methylation alterations were associated with genes in pathways involved in carcinogenesis, immune modulation, and immune signaling.Exposures to SHS in adulthood, childhood, occupationally, and in total are each significantly associated with changes in DNA methylation of several CpG loci in bladder tumors, adding biological plausibility to SHS as a risk factor for bladder cancer.

The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats and fatty acids and the risk of bladder cancer. A case–control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls, and OR and 95 % CI were calculated using unconditional logistic regression. Adjustment was made for potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of α-linolenic acid (ALA) (OR 0·26, 95 % CI 0·10, 0·65; P for trend = 0·01) and vegetable fat (OR 0·39, 95 % CI 0·18, 0·86; P for trend = 0·03). Borderline statistically significant reduced odds were detected for polyunsaturated fat (OR 0·43, 95 % CI 0·19, 0·98; P for trend = 0·07) and linoleic acid (OR 0·43, 95 % CI 0·19, 0·96; P for trend = 0·06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse association to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and quantities of different dietary fatty acids consumed.

OBJECTIVE: Although the effect of fruit and vegetables on the risk of bladder cancer has been widely studied, little is known about their micronutrient components. Our aim was to investigate associations between minerals and vitamins and bladder cancer. METHODS: A case-control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls using a 121-item food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression adjusting for sex, age, smoking characteristics, and energy intake. RESULTS: The ORs (95% CI) for highest quartile versus lowest quartile for total intake of vitamin E was 0.66 (0.36-1.20; p trend = 0.09) and 0.49 (0.21-1.17; p trend = 0.13) for dietary phosphorus. The odds of bladder cancer for heavy smokers with the highest total intake of vitamin E, carotenoids, and niacin were 0.58 (0.34-0.99), 0.62 (0.36-1.09), and 0.66 (0.39-1.14), respectively. Higher total intakes of carotenoids, vitamin D, thiamin, niacin, and vitamin E were inversely related to bladder cancer risk among older individuals. CONCLUSION: Our findings suggest further investigation of the effect of vitamin E, carotenoids, vitamin D, thiamin, and niacin on bladder cancer risk may be warranted. Future studies should focus on high risk groups such as heavy smokers and older individuals.

Chronic arsenic exposure at levels found in US drinking water has been associated with bladder cancer. While arsenic is a known carcinogen, recent studies suggest that it is useful as a therapeutic agent for leukemia. This study examined the relationship between arsenic exposure and bladder cancer mortality.We studied 832 cases of bladder cancer diagnosed in New Hampshire from a population-based case-control study. Individual exposure to arsenic was determined in home drinking water using ICP-MS and in toenail samples by instrumental neutron activation analysis.Among the high arsenic exposure group, found using toenail arsenic level or arsenic consumption, cases experienced a de-escalated survival hazard ratio (HR) [high (or =75 percent) versus low (25th percentile) toenail arsenic overall survival HR 0.5 (95% CI 0.4-0.8)], controlled for tumor stage, grade, gender, age and treatment regimen. This association was found largely among invasive tumors, in smokers and was not modified by TP53 status. Bladder cancer cause-specific survival showed a similar trend, but did not reach statistical significance [HR 0.5 (95% CI 0.3-1.1)].Arsenic exposure may be related to the survival of patients with bladder cancer.

Electrical properties of the prostate may provide sufficient contrast for distinguishing malignant and benign formations in the gland. We evaluated how well these electrical properties discriminate cancer from noncancer tissues in the prostate.Electrical admittivity (conductivity and permittivity) was recorded at 31 discrete frequencies of 0.1 to 100 kHz from each of 50 ex vivo human prostates. A specifically designed admittivity probe was used to gauge these electrical properties from sectioned prostate specimens. The specific tissue area probed was marked to provide precise colocalization between tissue histological assessment and recorded admittivity spectra.Adenocarcinoma, benign prostatic hyperplasia, nonhyperplastic glandular tissue and stromal tissue were the primary tissue types probed. Mean cancer conductivity was significantly less than that of glandular and stromal tissues at all frequencies (p0.05), while mean cancer permittivity was significantly greater than that of all benign tissues at 100 kHz (p0.0001). ROC curves showed that permittivity at 100 kHz was optimal for discriminating cancer from all benign tissues. This parameter had 77% specificity at 70% sensitivity and an ROC AUC of 0.798.The contrast in electrical admittivity properties of different prostate tissues shows promise for distinguishing cancer from benign tissues. Sensitivity and specificity exceed those reported for current prostate specific antigen screening practices at low prostate specific antigen, making this an attractive addition to the clinical armamentarium for identifying prostate cancer.

With an estimated 68 810 new cases in 2008, bladder cancer is the fifth most commonly diagnosed cancer in the United States of America (Scosyrev et al, 2009). Several risk factors have been identified as potential causes of bladder cancer, including tobacco use, occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons (Johansson and Cohen, 1997; Silverman et al, 2006), and treatment with cyclophosphamide (Kinlen, 1985; Baker et al, 1987; Radis et al, 1995; Volkmer et al, 2005). Glucocorticoids, often in combination with other immunosuppressive drugs, are a part of post-transplant therapy and alone are used to treat other acute or chronic inflammatory conditions, including rheumatoid arthritis, inflammatory bowel disease and asthma (Zoorob and Cender, 1998). There is evidence of an enhanced risk of certain types of cancer, including skin cancers and lymphomas, among organ transplant recipients (Birkeland et al, 1995, 2000; Kyllonen et al, 2000; Adami et al, 2003; Vajdic et al, 2006) and prolonged users of immunosuppressive drugs, such as glucorticoids, for other conditions (Karagas et al, 2001; Sorensen et al, 2004; Jensen et al, 2009). The incidence of bladder cancer is two- to four-fold higher among organ transplant recipients (Buzzeo et al, 1997); however, the risk among patients using oral glucocorticoids for other reasons is unknown. Therefore, we examined the potential risk of bladder cancer associated with glucocorticoid use in non-transplant recipients as part of an ongoing population-based case–control study of bladder cancer conducted in New Hampshire, USA.

Pseudolipomatosis is an artifactual microscopic change in tissues that resembles fatty infiltration, most often described in the gastrointestinal tract. The fatlike spaces represent air or gas bubbles that enter the mucosa through microscopic ruptures secondary to gaseous insufflation. We report a series of cases of pseudolipomatosis encountered in gynecologic tissues removed during hysteroscopic procedures, a finding not previously described. We identified 300 consecutive hysteroscopic procedures performed at our institution from 2006 to 2008. Patients' medical records were reviewed to collect pertinent clinical data. Slides from all cases were systematically reviewed. The diagnosis of pseudolipomatosis was established by consensus. Twenty-eight cases of pseudolipomatosis, representing 9.3% of patients who under went hysteroscopy, were identified. Pseudolipomatosis was found in 9 endometrial curettings or biopsy tissues, 8 endometrial or endocervical polyps, 8 uterine fibroids, 2 fallopian tubes, and 1 endocervical biopsy. The type of distention medium used and length of hysteroscopic procedure did not differ significantly between cases with and without pseudolipomatosis. Pseudolipomatosis vacuoles varied in distribution from crowded clusters to sparsely scattered and solitary. Occasionally, vacuoles were found in vascular channels. Vacuoles were round or ovoid, unilocular, and variable in size. Immunohistochemical staining for adipocyte and endothelial markers were negative. We hypothesize that pseudolipomatosis derives from air that is almost invariably introduced into the uterus during media insufflation for hysteroscopy, creating a bubble under pressure. The air enters tissues either through lining microruptures or during the biopsy procedure. Pseudolipomatosis is a relatively common, easily overlooked finding in hysteroscopically derived specimens that may be misdiagnosed when prominent.

Purpose: To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-α 2a in metastatic renal cell carcinoma patients. Experimental Design: Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 × 107 cells/1 mL Lactated Ringer's solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-α 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti–renal cell carcinoma antibody and cytokine levels. Results: All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4+ T regulatory cells had a strong association with outcome. Pre–IP-10 serum levels approached significance for predicting outcome. Conclusions: The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.

Human polyomavirus infection, which can be detected morphologically on Pap-stained routine urine cytology specimens, is most commonly encountered in immunocompromised patients and is a well-described complication of renal transplantation. We present a case of an immunocompetent 5-year-old boy with a sudden onset of dysuria and hematuria due to a self-limited polyomavirus urinary tract infection detected on routine urine cytology and confirmed with real-time PCR. Although rare cases of nonhemorrhagic cystitis have been reported, to the best of our knowledge this is the first case of hemorrhagic cystitis occurring in this setting. Diagn. Cytopathol. 2008;36:375–378. © 2008 Wiley-Liss, Inc.

The WHO/International Society of Urological Pathology classification of bladder cancer, introduced in 1998, differs from the traditional 1973 WHO classification. Few studies have reported survival data based on the WHO/International Society of Urological Pathology classification and none has demonstrated clear superiority compared to the 1973 WHO system. In a large, nonselected population of patients with bladder cancer we rated all incident tumors using each system and compared long-term patient survival.New Hampshire residents with bladder cancer diagnosed between 1994 and 2000 were identified through the State Cancer Registry. Slides were retrieved from more than 90% of cases and reviewed by a single pathologist. Tumors were classified according to WHO and WHO/International Society of Urological Pathology criteria. Overall patient survival was determined for the cohort of 504 patients after an average of 7 years using a national mortality database.For both grading systems there was a gradient of progressively lower survival times from the lowest grade to the highest grade tumors. Hazard ratios and 95% confidence intervals for the WHO/International Society of Urological Pathology system were 1.9 (1.0-3.4) for low grade papillary urothelial carcinoma and 3.0 (1.5-6.0) for high grade papillary urothelial carcinoma, compared to papillary urothelial neoplasms of low malignant potential. For the WHO (1973) system compared to grade 1 tumors the hazard ratio for grade 2 tumors was 1.8 (1.1-3.1) and for grade 3 was 2.4 (1.2-4.7).Advantages of the WHO/International Society of Urological Pathology bladder tumor classification include more detailed diagnostic criteria, the ability to define a lesion with minimal malignant potential and the ability to identify a larger group of patients needing closer surveillance. However, we found that the WHO/International Society of Urological Pathology tumor categories did not detect a clear overall survival advantage compared to the WHO (1973) classification system.