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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

OBJECTIVE: To evaluate treatment with methotrexate (MTX) in patients with newly diagnosed giant cell arteritis (GCA) to determine if MTX reduces GCA relapses and cumulative corticosteroid (CS) requirements and diminishes disease- and treatment-related morbidity. METHODS: This was a multicenter, randomized, double-blind study. Over 4 years, 16 centers from the International Network for the Study of Systemic Vasculitides enrolled patients with unequivocal GCA. The initial treatment was 1 mg/kg/day (

Background: Bladder cancer mortality rates have been elevated in northern New England for at least five decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than the United States overall. We explored reasons for this excess, focusing on arsenic in drinking water from private wells, which are particularly prevalent in the region. Methods: In a population-based case-control study in these three states, 1213 bladder cancer case patients and 1418 control subjects provided information on suspected risk factors. Log transformed arsenic concentrations were estimated by linear regression based on measurements in water samples from current and past homes. All statistical tests were two-sided. Results: Bladder cancer risk increased with increasing water intake ( Ptrend = .003). This trend was statistically significant among participants with a history of private well use ( Ptrend = .01). Among private well users, this trend was apparent if well water was derived exclusively from shallow dug wells (which are vulnerable to contamination from manmade sources, Ptrend = .002) but not if well water was supplied only by deeper drilled wells ( Ptrend = .48). If dug wells were used pre-1960, when arsenical pesticides were widely used in the region, heavier water consumers (>2.2 L/day) had double the risk of light users (

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case 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.

Unusual vulvar neoplasms comprise a small minority of general surgical pathology cases. We have limited our discussion to the following four vulvar tumours that were diagnosed at our institution during the past year: extramammary Paget disease; melanoma; granular cell tumour; and epithelioid sarcoma, proximal-type. We hope that the review will be of practical interest to the general surgical pathologist. Pathogenesis, clinical presentation, morphology, differential diagnosis, ancillary studies, prognosis, and treatment will be discussed.

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.

Hypermethylation of tumor suppressor genes is central to the pathogenesis of human malignancy, yet this alteration's etiology remains unclear, and its clinical impact has not yet been studied using an approach that can yield directly generalizable results. Therefore, we sought to examine both of these issues in bladder cancer, seeking to understand the characteristics of epidemiologically well-defined patient tumors with differing levels of methylation silencing. We analyzed epigenetic silencing of 16 genes in a population-based incident case series of 331 bladder transitional cell carcinomas. We utilized a novel item response theory (IRT) model, to examine, in an unbiased fashion, the relationship of patient characteristics, carcinogen exposure history and tumor characteristics with the underlying propensity for gene hypermethylation. Age, male gender and current cigarette smoking were significantly positively associated with the methylation latent trait. Promoter hypermethylation as a latent trait significantly predicted both non-invasive/high-grade and invasive stage disease and was also significantly associated with survival, with each unit increase in the latent trait resulting in a 30% increase in the risk of death. This work, studying all stages and grades of incident bladder cancer, provides definitive evidence that carcinogen exposures play a critical role in selecting these alterations in tumorous clones and that epigenetic silencing is a strong and significant predictor of tumor stage and overall patient survival. Finally, our novel approach provides insight into the etiology of promoter hypermethylation, suggesting that selected, carcinogen-exposed individuals have a greater propensity for hypermethylation that is associated with more aggressive, fatal disease.

Contains fulltext : 167299.pdf (Publisher’s version ) (Closed access) Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P

Background MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use. Methods We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between media. Results Numerous microRNAs were detected and overlapping from specific bio-specimen sources. MiR-4454 and miR-21 overexpression was found in three sources: tumor, WBCs and urine. Additionally, miR-15b-5p, miR-126-3p, miR-93-5p, and miR-150-5p were common to tumor/WBCs, while miR-720/3007a, miR-205, miR-200c-3p and miR-29b-3p common to tumor/urine. Significant associations were noted between the log-adjusted average miRNA counts in tumor vs. WBCs (r = 0.418 p

Prostate cancer (PCa) has a high 10-year recurrence rate, making PCa the second leading cause of cancer-specific mortality among men in the USA. PCa recurrences are often predicted by assessing the status of surgical margins (SM) with positive surgical margins (PSM) increasing the chances of biochemical recurrence by 2-4 times. To this end, an SM assessment system using Electrical Impedance Spectroscopy (EIS) was developed with a microendoscopic probe. This system measures the tissue bioimpedance over a range of frequencies (1 kHz to 1MHz), and computes a Composite Impedance Metric (CIM). CIM can be used to classify tissue as benign or cancerous. The system was used to collect the impedance spectra from excised prostates, which were obtained from men undergoing radical prostatectomy. The data revealed statistically significant (p

Positive surgical margins (PSMs) found following prostate cancer surgery are a significant risk factor for post-operative disease recurrence. Noxious adjuvant radiation and chemical-based therapies are typically offered to men with PSMs. Unfortunately, no real-time intraoperative technology is currently available to guide surgeons to regions of suspicion during the initial prostatectomy where immediate surgical excisions could be used to reduce the chance of PSMs. A microendoscopic electrical impedance sensing probe was developed with the intention of providing real-time feedback regarding margin status to surgeons during robot-assisted laparoscopic prostatectomy (RALP) procedures. A radially configured 17-electrode microendoscopic probe was designed, constructed, and initially evaluated through use of gelatin-based phantoms and an ex vivo human prostate specimen. Impedance measurements are recorded at 10 frequencies (10 kHz - 100 kHz) using a high-speed FPGA-based electrical impedance tomography (EIT) system. Tetrapolar impedances are recorded from a number of different electrode configurations strategically chosen to sense tissue in a pre-defined sector underlying the probe face. A circular electrical impedance map (EIM) with several color-coded pie-shaped sectors is created to represent the impedance values of the probed tissue. Gelatin phantom experiments show an obvious distinction in the impedance maps between high and low impedance regions. Similarly, the EIM generated from the ex vivo prostate case shows distinguishing features between cancerous and benign regions. Based on successful development of this probe and these promising initial results, EIMs of additional prostate specimens are being collected to further evaluate this approach for intraoperative surgical margin assessment during RALP procedures.

Methods (Expanded) (DOCX 112 kb)

Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism ( interaction ≤ .001), rs11892031 ( UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 ( TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 ( TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis.

With the rise in detection of incidental renal masses on imaging, there has been a commensurate rise in the use of percutaneous biopsies for evaluation of these tumours. Tumour tract seeding had previously been one of the most feared complications of percutaneous biopsy of renal cell carcinoma (RCC). Recently, less emphasis has been placed on this complication, with the assertion that it has only been reported eight times in literature, and thus must be exceedingly rare. However, we report two cases of tumour tract seeding associated with percutaneous biopsy and treatment of RCC over a short time period at a single institution. This report challenges the current extremely low estimates of the frequency of this complication and calls for a more realistic assessment.

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Primary carcinoid tumors are rare neoplasms of the ovary. Of the 4 histologic subtypes, ovarian carcinoid tumors with insular patterns produce carcinoid syndrome in approximately one third of cases, versus strumal and trabecular carcinoids which very rarely cause typical carcinoid syndrome. A unique presentation of ovarian carcinoid tumors with concurrent severe constipation has been reported, which is thought to represent a new carcinoid syndrome. The proposed mechanism is the production of peptide YY by the tumor, a gastrointestinal hormone responsible for decreasing gut motility. We report a case of a 34-yr-old white woman who presented with constipation and weight loss for 1 yr, and was found to have a unilateral ovarian strumal carcinoid, which produced peptide YY as demonstrated by immunohistochemistry. The 13 previous case reports of ovarian carcinoids with constipation are reviewed and the clinicopathologic features are discussed. This report and literature review further solidifies this entity as a new type of carcinoid syndrome.

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0-6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2-0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D' = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7-3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene-gene and gene-environment interactions.

BACKGROUND Somatic loss of the 9q allele as well as alteration of the tumor suppressor p53 occurs commonly in bladder cancers. Although alteration of p53 has been strongly associated with invasive stage disease, the prognostic significance of 9q loss of heterozygosity (LOH) and the relations between these alterations are less well defined. METHODS The 9q LOH was examined at five microsatellites and p53 alterations (mutation and persistent immunohistochemical staining) in a population-based case series of 271 newly diagnosed bladder cancer patients. Loss of heterozygosity was scored quantitatively and p53 mutation completed using single-strand conformation polymorphism screening followed by sequencing. RESULTS Overall, allelic loss at 9q was detected in 74.5% (202/271) of cases and allele loss was associated with invasive disease (P < 0.05). Although based on small numbers, all nine in situ lesions contained 9q LOH. Age, gender, and smoking were not significantly associated with chromosome 9q allele loss. Both intense persistent p53 staining and LOH at 9q were independently associated with invasive disease (P < 10−14 and P < 0.05, respectively). CONCLUSIONS These data, using a population-based sample, suggest a relation between 9q LOH and invasive stage bladder cancer, and thereby suggests that a tumor suppressor gene at this loci, in addition to p53, may be important in the development of this more aggressive form of the disease. Cancer 2005. © 2005 American Cancer Society.

We used real-time polymerase chain reaction (PCR) technology to detect BK virus (BKV) in H and E-stained kidney biopsy sections, using laser capture microdissection. Renal allograft biopsy specimens from 4 patients with the histopathologic diagnosis of BKV-associated nephropathy (BKVAN; group 1) and 3 patients suspected to have BKVAN but without diagnostic histologic features (group 2) were retrieved. Diagnostic inclusion-bearing cells were microdissected by laser capture microscopy from group 1. Renal tubular epithelial cells were microdissected randomly in group 2. DNA was extracted and real-time amplification performed using primers targeting the large "T" and small "t" regions of the BKV and JC virus genomes. Tubular epithelial cells from a case without evidence of BKV infection were used as negative controls in a similar reaction. BKV presence was demonstrated only in epithelial cells containing typical viral inclusions. Group 2 and negative control samples were confirmed as negative for BKVAN. Real-time PCR technology can be used to detect BKV in H and E-stained, paraffin-embedded tissue sections. This technique detected BKV in tubular epithelial cells of renal allografts. To our knowledge, this is the first report of detecting BKV in laser capture microdissected renal biopsy specimens using real-time PCR.

Functional variants in the methylenetetrahydrofolate reductase (MTHFR) gene, including the 677C>T and 1298A>C polymorphisms, have been associated with a moderately reduced risk of several cancers, including colorectal cancers. While recent studies have investigated the role of these polymorphisms on bladder cancer susceptibility, results have been mixed. To clarify the role of MTHFR polymorphisms on bladder cancer risk, we genotyped MTHFR 677C>T and MTHFR 1298A>C in a population-based study of bladder cancer of 352 patients and 551 controls from New Hampshire, USA. The allelic frequency was 35.6% for MTHFR 677C>T and 40.4% for MTHFR 1298A>C among controls. We found no evidence of a main gene effect for either polymorphism (adjusted OR for MTHFR 677C>T variants versus the reference genotype=1.1; 95% CI, 0.8–1.4 and adjusted OR for MTHFR 1298A>C variants versus the reference genotype=1.0; 95% CI, 0.7–1.4). Odds ratios did not appear to differ by smoking status or gender. We observed differences in the risk estimates for the MTHFR polymorphisms by arsenic exposure, but they were not statistically significant ( P = 0.67 for MTHFR 677C>T and P = 0.12 for MTHFR 1298A>C). Thus, our findings do not support the presence of a main gene effect. The possibility that MTHFR polymorphism affects susceptibility to environmental exposures warrants further consideration.

In the United States each year, almost 13,000 deaths are attributable to bladder cancer, with the majority of these deaths related to higher stage, muscle-invasive solid tumors. Epigenetic silencing of the secreted frizzled receptor proteins (SFRP), antagonists of the WNT pathway, leads to constitutive WNT signaling, altering cell morphology and motility. Identifying alterations in this pathway in bladder cancer may prove useful for defining the invasive phenotype and provide targets for guiding therapy. Using a population-based study of bladder cancer (n = 355), we examined epigenetic alterations, specifically gene promoter hypermethylation, of four SFRP genes in addition to immunohistochemical staining of TP53, which has been previously shown to be a predictor of invasive disease. We observed a significant linear trend (P < 0.0004) in the magnitude of the risk of invasive disease with the number of SFRP genes methylated. Both TP53 alteration and SFRP gene methylation showed significant independent associations with invasive bladder cancer. Strikingly, in examining the joint effect of these alterations, we observed a >30-fold risk of invasive disease for patients with both altered SFRP gene methylation and intense TP53 staining (odds ratio, 32.1; P < 10−13). Overall patient survival was significantly poorer in patients with any SFRP genes methylated (P < 0.0003) and in proportional hazards modeling, patients with methylation of any SFRP gene had significantly poorer overall survival (hazard ratio, 1.78; P < 0.02) controlled for TP53 staining intensity and other survival-associated factors. Classifying tumors based on SFRP methylation status and TP53 protein staining intensity may be a clinically powerful predictor of invasive, deadly disease.

Objective: Urethrocutaneous fistula is a well-known complication of hypospadias surgery and is reported in 5–10% of repairs. Using a previously described juvenile pig model, we present a histological analysis of the healing of the ventral aspect of the urethral repair and describe the histological mechanism of fistula formation. Materials and Methods: Twelve juvenile pigs underwent ventral, longitudinal urethral incision and closure over a 5-French feeding tube. The ventral aspect was closed in running fashion using two closure techniques and three suture types in each animal. Three animals were sacrificed on postoperative day 3, three on day 5, three on day 12, one on day 14, and two on day 21. Closure was one-layered incorporating urethral mucosa in the animals sacrificed on days 3, 5, and 21. An extra-mucosal suture technique was used in the group sacrificed on day 12. Sections of the penis were cut, paraffin embedded, and treated with Hematoxylin and Eosin staining. Results: Fistulae were seen in 12 specimens and in association with each suture type. Fewer sections of the extra-mucosal technique showed fistulization. Fistulae lined with immature epithelium were seen by day 5. Mature fistulae were observed by day 12. Skin epithelium and urethral mucosa migrated along suture tracts. By days 12 and 21, in addition to mature fistulae, several sections showed well-healed ventral repairs with clearly extramucosal suture tracts. Conclusions: Fistula formation begins early in the healing process after ventral urethral repair. Incorporation of urethral mucosa in the ventral repair is a substrate for fistula formation with rapid migration of urethral mucosa and skin epithelium into suture tracts. The importance of a multi-layered repair and extra-mucosal suture technique are thus emphasized with respect to urethral repair. Whether the mucosal or dermal migration along suture tracts can be attenuated or prevented by changing the biochemical environment awaits further investigation.

The molecular pathology of bladder cancer has been the subject of considerable interest and mutation of the p53 gene, which has been associated with more invasive bladder cancer, has been widely studied. Further, there is evidence that p53 inactivation (either mutation or protein dysregulation), independent of stage, may be predictive of bladder cancer progression. In an effort to avoid possible biases associated with selection of more advanced cases, we examined p53 inactivation in a population-based study of bladder cancer in New Hampshire, using both mutation and immunohistochemical methods. We found the overall prevalence of mutation to be approximately 10%, while immunohistochemical analysis suggests that approximately 66% of the tumours have dysregulated p53 at the protein level. There was a significant association of mutation with persistent p53 staining, but there remained a marked number of tumours discordant for mutation and aberrant p53 immunohistochemistry. Based upon immunohistochemical staining alone, intensity rather than extent of p53 staining was more strongly related to tumour invasiveness. Additionally, all tumours with a mutation in exon 8 stained intensely. Taken together, this suggests that intense staining represents a distinct phenotype of dysfunctional protein. Our data indicate that population-based approaches to somatic alteration of p53 in bladder cancer are crucial to understanding the relationship of p53 changes to aetiology and the outcome of this disease, and further suggest that the pattern of immunohistochemical staining may represent distinct, discernible phenotypes. British Journal of Cancer (2004) 90, 1572-1576. doi:10.1038/sj.bjc.6601748 www.bjcancer.com Published online 6 April 2004