Diet quality, common genetic polymorphisms, and bladder cancer risk in a New England population-based study.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk.

Diet Quality and Survival in a Population-Based Bladder Cancer Study.

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.

Identification of Let-7f-5p as a novel biomarker of recurrence in non-muscle invasive bladder cancer.

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.

A Machine Learning Approach for Long-Term Prognosis of Bladder Cancer based on Clinical and Molecular Features.

Improving the consistency and reproducibility of bladder cancer prognoses necessitates the development of accurate, predictive prognostic models. Current methods of determining the prognosis of bladder cancer patients rely on manual decision-making, including factors with high intra- and inter-observer variability, such as tumor grade. To advance the long-term prediction of bladder cancer prognoses, we developed and tested a computational model to predict the 10-year overall survival outcome using population-based bladder cancer data, without considering tumor grade classification. The resulted predictive model demonstrated promising performance using a combination of clinical and molecular features, and was also strongly related to patient overall survival in Cox models. Our study suggests that machine learning methods can provide reliable long-term prognoses for bladder cancer patients, without relying on the less consistent tumor grade. If validated in clinical trials, this automated approach could guide and improve personalized management and treatment for bladder cancer patients.

Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.

BACKGROUND: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence). OBJECTIVE: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes. METHODS: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors. RESULTS: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 µg/m3-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 µg/m3-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019). CONCLUSIONS: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.

MicroRNA Dysregulation and Non-Muscle-Invasive Bladder Cancer Prognosis.

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, (P adj = 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 (P adj = 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.

Comparative study of separation between ex vivo prostatic malignant and benign tissue using electrical impedance spectroscopy and electrical impedance tomography.

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.

VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis.

OBJECTIVE: The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V-domain Ig-containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1α) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathway is a novel strategy for the treatment of human autoimmune disease, and therefore we undertook this study to determine the impact of VISTA genetic deficiency on lupus development in a lupus-prone mouse strain. METHODS: To evaluate whether genetic deficiency of VISTA affects the development of lupus, we interbred VISTA-deficient mice with Sle1.Sle3 mice, a well-characterized model of systemic lupus erythematosus (SLE). RESULTS: We demonstrated that the development of proteinuria and glomerulonephritis in these mice, designated Sle1.Sle3 VISTA-/- mice, was greatly accelerated and more severe compared to that in Sle1.Sle3 and C57BL/6 VISTA-/- mice. Analysis of cells from Sle1.Sle3 VISTA-/- mice showed enhanced activation of splenic CD4+ T cells and myeloid cell populations. No increase in titers of autoantibodies was seen in Sle1.Sle3 VISTA-/- mice. Most striking was a significant increase in proinflammatory cytokines, chemokines, and interferon (IFN)-regulated genes associated with SLE, such as IFNα, IFNγ, tumor necrosis factor, interleukin-10, and CXCL10, in Sle1.Sle3 VISTA-/- mice. CONCLUSION: This study demonstrates for the first time that loss of VISTA in murine SLE exacerbates disease due to enhanced myeloid and T cell activation and cytokine production, including a robust IFNα signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus.

Prostate Cancer Detection Using Composite Impedance Metric.

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.

MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer.

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 < 0.001), and tumor vs. urine (r = 0.38 p < 0.001). No association was seen tumor vs. plasma exosome miRs (r = 0.07 p = 0.06). CONCLUSIONS: MicroRNA profiling from matched samples in patients shows a significant number of microRNAs up regulated in bladder tumors are identifiable in urine exosomes and WBCs of the same patient, but not in blood plasma. This study demonstrated varying relationships between miRNA detected in biological media from the same patient, and serves to inform the potential of urine-based microRNAs as biomarkers for bladder cancer and potentially other malignancies.

3D Microendoscopic Electrical Impedance Tomography for Margin Assessment During Robot-Assisted Laparoscopic Prostatectomy.

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 ( σinclusion = 1 S/m) are positioned at various locations within a hemispherical background ( σbackground = 0.1 S/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 ( σsaline = 0.1 S/m) with a position and area error of 0.46 mm and 0.84 mm2, 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.

Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence.

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.

Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature.

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.

A single-centre experience with tumour tract seeding associated with needle manipulation of renal cell carcinomas.

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.

Genetic polymorphisms modify bladder cancer recurrence and survival in a USA population-based prognostic study.

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.

Body mass and smoking are modifiable risk factors for recurrent bladder cancer.

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/m(2) ) 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.

Genetic variant as a selection marker for anti-prostate stem cell antigen immunotherapy of bladder cancer.

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.

Ureteroscopic biopsy of upper tract urothelial carcinoma using a novel ureteroscopic biopsy forceps.

INTRODUCTION: We sought to assess the adequacy of surgical specimens obtained utilizing the BIGopsy (Cook Medical, Bloomington, IN, USA) biopsy forceps both ex vivo and in vivo and compare them to traditional 3Fr biopsy forceps in patients with suspected upper tract urothelial carcinoma. MATERIALS AND METHODS: Patients undergoing nephroureterectomy for suspected upper tract transitional cell carcinoma were recruited. Surgical specimens, immediately after extirpation were examined and alternatively biopsied ex vivo with the BIGopsy and 3Fr biopsy forceps. We then retrospectively reviewed our most recent experience with ureteroscopic biopsy. The biopsy device, size, depth, grade, stage, pathologic diagnosis and subjective biopsy quality were assessed. RESULTS: Three ex vivo nephroureterectomy specimens were evaluated. The average biopsy size from the 3Fr biopsy forceps was 3.5 +/- 2.8 mm2 and for the BIGopsy was 31.2 +/- 34.6 mm2. Subjectively, the BIGopsy specimens revealed less distortion and fragmentation and were easier to interpret by the pathologist. Sixteen patients underwent 19 ureteroscopic procedures. The mean size in maximal diameter (mm +/- SD) of the biopsies in each group were; 3Fr 1.2 +/- 0.4, BIGopsy 3.4 +/- 2.0, nitinol basket 4.9 +/- 4.0 and laser 11 +/- 8.5. Lamina propria was identified in 3/13 (23%) biopsies with 3Fr biopsy forceps, 6/11 (55%) biopsies with the BIGopsy forceps, 6/8 (75%) biopsies with the nitinol basket and 2/2 (100%) biopsies with the holmium laser. Six patients underwent biopsies with both the BIGopsy and 3Fr biopsy forceps. A definitive diagnosis was made in 2/6 cases with the 3Fr biopsy forceps compared with all 6/6 cases with the BIGopsy biopsy forceps. Grade and stage matched final surgical grade and stage in 3/3 cases biopsied with the BIGopsy. CONCLUSION: For lesions with stalks, the holmium laser and basket biopsy provided larger specimens than either of the forceps. For flat or sessile lesions, the BIGopsy biopsy forceps provided larger, deeper less distorted specimens than the 3Fr biopsy forceps and correlated well with ultimate grade and stage. Improved biopsy quality may translate into improved ability to diagnose both benign and malignant ureteral and renal pelvic mucosal lesions endoscopically.