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188 Background: Many patients with a negative prostate biopsy (PBx) but persistent clinical suspicion of prostate cancer (PCa) undergo repeat PBx. Although higher rates of low grade PCa on repeat PBx have been reported, we hypothesize that a considerable risk of clinically significant PCa remains. Methods: We retrospectively reviewed the data from a cohort of 25,584 patients who underwent one or more PBx at two institutions. To ensure current standards, we only included patients biopsied from 2004 to 2010 with a minimum of ten cores taken. Statistical analysis was performed using SPSS v.17.0. Results: 6,729 men met the inclusion criteria, 764 (11.4%) of whom underwent a second PBx after negative initial biopsy. Overall, 3669 (54.6%) men were diagnosed with PCa on first PBx whereas 199 (26.0%) had a positive second PBx (p Conclusions: Despite having a negative initial PBx, over a quarter of men who underwent a repeat biopsy in our large cohort had PCa detected. Despite the pathologic characteristics being more favorable on repeat PBx, almost two-thirds of these men still had intermediate or high-risk PCa. In conclusion, men in whom there is persistent suspicion for PCa despite a negative PBx should be counseled that repeat biopsies detect a high number of clinically significant PCa. [Table: see text]

281 Background: The aim of the current study was to assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters in a large multicenter cohort of patients with LN metastasis (LNM) following radical nephroureterectomy (RNU). Methods: Retrospective analysis of 222 patients with LNM treated with RNU for upper tract urothelial carcinoma (UTUC) without neoadjuvant therapy. Microscopically, each LN metastasis was evaluated for presence of ENE. Results: The median number of LNs removed, number of positive LNs, and LN density were 4 (IQR: 8), 2 (IQR: 2), and 51.3% (IQR: 71.7%), respectively. Overall, 110 patients (49.5%) had ENE. Presence of ENE was associated with more advanced pT stage (p=0.026). In multivariable analyses, ENE was associated with disease recurrence (p=0.01) and cancer-specific mortality (p=0.013). LN density, when stratified by 30% cutoff, was associated with disease recurrence and cancer-specific mortality (p=0.048 and p=0.049) in univariable, but not in multivariable analyses. Addition of ENE to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p Conclusions: ENE is a powerful predictor of clinical outcomes in UTUC patients with LNM. While other LN parameters seem to have limited clinical value, ENE could help risk stratify UTUC patients with LNM for better counseling and clinical trial design.

274 Background: Serine peptidase inhibitor Kazal type 1 (SPINK1) overexpression has been associated with poor outcomes. In one small study, loss of SPINK1 expression in urothelial carcinoma of the bladder (UCB) was associated with advanced tumor stage. We assessed the expression of SPINK1 in normal urothelium and UCB and analysed the association of SPINK1 with pathological features and clinical outcomes of patients treated with radical cystectomy (RC). Methods: The study used TMAs containing samples from 438 consecutive UCB patients treated with RC. 62 cases of normal urothelium were included as controls. A monoclonal antibody was used for immunohistochemical SPINK1 staining. SPINK1 expression of UCB was evaluated by two pathologists, blind to clinical outcome. Samples demonstrating less than 50% staining extent and 0 to 1 intensity (scale 0 to 3), were considered to have loss of expression. Results: SPINK1 expression was noted in umbrella cells of normal urothelium in 32/62 controls (52%). UCB of 254 patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with advanced pathological stage (p=0.002) and presence of lymph node (LN) metastasis (p=0.04). Within a median follow-up of 130 month (IQR 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (5-year RFS: 52±3 vs. 61±4 months; p=0.02) and cancer-specific mortality (5-year CSS: 59±3 vs. 68±3 months; p=0.03). In multivariable Cox regression analyses that adjusted for the effects of age, gender, tumor stage and grade, concomitant CIS, LN status and adjuvant chemotherapy, SPINK1 was not associated with disease recurrence (p=0.09) or cancer-specific death (p=0.12). Conclusions: While umbrella cells in normal urothelium commonly expresses SPINK1, more than half of UCB specimen exhibit loss of SPINK1 expression. Loss of SPINK1 expression is strongly correlated with local disease stage and LN metastasis. SPINK1 revealed no independent prognostic value for outcome prognostication, but it is a very promising marker for tumor staging which could be used for tailored follow-up protocols and possibly as a target for therapy as it has similarities with epidermal growth factor.

267 Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. Methods: Our study included 2,244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant CIS. The cohort was split for development (12 centers, n=1273) and external validation (11 centers, n=971). Results: At a median follow-up of 45 months, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p-for-trend Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be utilized for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

Hematoxylin and eosin (H&E)-stained histology from thin sections of tissue obtained from preserved (frozen or formalin-fixed) specimens is the current gold standard for all histopathological diagnoses and intra-surgical margin assessments. While these methods are highly reliable, they have lengthy time requirements (processing, sectioning, staining, and reading by pathologists). Although efforts at digitization of glass slides are in progress, most pathologists still read analog slides; therefore, automated morphometry and real time online consultations are rare. Furthermore, the 2-dimensional nature of histology slides precludes assessment of 3-dimensional tissue architecture without time consuming serial sectioning. Now, however, Multiphoton microscopy (MPM), a nonlinear imaging technology, allows nearly instant imaging of fresh (unpreserved, unsectioned, and unstained) tissue based on spectrally resolved intrinsic tissue emission (ITE) signals, allowing the generation of 3-dimensional histology of the tissue at sub-micron lateral resolution, and up to 0.5 mm below the surface. The main components of ITE are: (1) autofluorescence arising from various cell cytoplasm components and elastin fibers; and (2) Second Harmonic Generation (SHG), a nonlinear scattering signal from collagen bundles and oriented microtubules. Using a single excitation wavelength and collecting emission signals using wavelength bandpass filters or spectroscopes, SHG and various autofluorescence components can be separately acquired and analyzed, as well as color coded and merged for easy visualization. Using such approaches, we have analyzed ex vivo tissue from human diagnostic and surgical biopsies, and from sections of excised human and rodent (rats and mice) organs (bladder, prostate, seminal vesicles, vasa deferentia, kidney, testis, colon, thyroid, tonsil, skin, bone and cartilage). In all cases, relevant tissue structures, including cells, collagen, elastin, fat, nerves and blood vessels have been identified. All specimens imaged by MPM have been subsequently subjected to H&E histopathology, and scanned images from the slides have been archived. Beginning with transurethral biopsy of bladder tumor (TURBT) specimens, we have begun the generation of a pathologist-annotated digital atlas containing both the MPM images and the corresponding H&E histopathology. Blinded diagnostic accuracy studies involving several pathologists and in some cases non-pathologists (e.g., surgeons in the context of margin assessments) are currently in progress, with encouraging preliminary results. Extension of MPM diagnostics to additional organs is being explored successfully by application to selected transgenic mice and to diseased veterinary animal subjects at the College of Veterinary Medicine at Cornell University. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4884. doi:10.1158/1538-7445.AM2011-4884

203 Background: There are no published nomograms that predict prostate cancer in a screened population. We describe three nomograms that predict for prostate cancer on biopsy derived from a large screening population. Methods: Patients from the Tyrol screening study of known age, total prostate-specific antigen (tPSA), digital rectal examination (DRE), prostate volume, and percent free PSA (%fPSA), and who underwent an initial prostate biopsy from January 1992 to June 2004, were included (n=2271). Multivariable logistic regression models were used to develop the biopsy positivity predictive nomograms: nomogram 1- age, DRE, tPSA; nomogram 2- age, DRE, tPSA, prostate volume; nomogram 3- age, DRE, tPSA, prostate volume, %fPSA. The predictive accuracy of the models was assessed in terms of discrimination and calibration. External validation of the nomograms was performed by comparison with a urologically referred population of patients who underwent prostate biopsy (n=599). Results: All three nomograms discriminated well between biopsy positive and biopsy negative patients for both the screening and urologically referred cohorts (nomogram 3 better than nomogram 2 better than nomogram 1). All three nomograms were well calibrated internally, but the nomograms under-predicted the probability of a positive biopsy in the urologically referred cohort. Conclusions: Our nomogram based on age, total PSA, and DRE has a good predictive ability to differentiate between screened patients that will show cancer on initial prostate biopsy and those that will not. Adding prostate volume and percent free PSA improves this predictive power further. All three nomograms under-predict prostate cancer in a urologically referred cohort. These simple nomograms may be of value in counseling screened men with raised PSA and/or abnormal DRE regarding the need for biopsy. No significant financial relationships to disclose.

249 Background: The outcomes of patients with non-muscle-invasive urothelial carcinoma of the bladder (NMIUCB) remain poorly understood. The aim of our study was to identify prognostic factors of cancer recurrence and progression in patients with primary UCB. Methods: We performed a combined analysis on individual data from 4,325 patients with primary NMIUCB. Results: Within a median follow-up of 64 months, 1,960 patients (45.4%) experienced disease recurrence, 498 (11.5%) experienced progression to muscle-invasive stage, 1,155 (26.7%) died of any cause, and 310 (7.2%) died of their cancer. In multivariable Cox regression analysis, advanced age, higher grade, larger tumor size, higher number of tumors, number of prior recurrences, and type of intravesical therapy were independent predictors of disease recurrence and progression. While treatment intravesical chemotherapy was only associated with decreased/delayed cancer recurrence, intravesical BCG therapy was associated with decreased/delayed cancer recurrence and progression. The predictive accuracies of the models for recurrence and progression were 63.5% and 71.3%, respectively. Conclusions: Even in a heterogenous patient population, BCG therapy appears to decrease frequency and delay time to cancer recurrence and progression in patients with NMIUCB. Predictive tools based on combination of multiple clinical variables which capture the biological and clinical potential of nonmuscle-invasive disease could help with patient counseling and individualized risk assessment for adjuvant intravesical therapy and clinical trial design. [Table: see text] No significant financial relationships to disclose.

According to international standards, cardiac pacemakers have to indicate the status of their batteries upon magnet application by specific stimulation patterns. The purpose of this study has been to assess whether this concept can be used as a basis for automated and manufacturer independent examination of the depletion level of pacemakers in the framework of a collaborative telemedical pacemaker follow-up system. A prototype of such a system was developed and tested in a real clinical environment. Electrocardiograms (ECGs) were recorded during magnet application and automatically processed to extract the specific stimulation patterns. The results were used to assign each signal a corresponding pacemaker status: "ok," "replace" or "undefined," based on the expected behavior of the devices as specified by the manufacturer. The outcome of this procedure was compared to the result of an expert examination, resulting in a positive predictive value of 100% for the detection of ECGs indicating pacemaker status "ok." The method can, therefore, be utilized to quickly, safely and manufacturer neutrally classify cases into the categories "ok" and "needs further checking," which - in a telemedical setting - may be used to increase the efficiency of pacemaker follow-up procedures in the future.