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Objective Increased computational power and improved visualization hardware have generated more opportunities for virtual reality (VR) applications in healthcare. In this study, we test the feasibility of a VR-assisted surgical navigation system for robotic-assisted radical prostatectomy. Material and methods The prostate, all magnetic resonance imaging (MRI) visible tumors, and important anatomic structures like the neurovascular bundles, seminal vesicles, bladder, and rectum were contoured on a multiparametric MRI using an in-house segmentation software. Three-dimensional (3-D) VR models were rendered and evaluated in a side room of the operating room. While interacting with the VR platform, a real-time stereo video capture of the in situ prostate was obtained to render a second 3-D model. The MRI-based model was then overlaid on the real-time model by using an automated alignment algorithm. Results Ten patients were included in this study. All MRI-based VR models were examined by surgeons immediately prior to surgery and at important steps where visualization of the tumors and their proximity to surrounding anatomic structures were critical. This was mainly during the preparation of the prostatic pedicles, neurovascular plexus, the apex, and bladder neck. All participants found the system useful, especially for tumors with locally aggressive growth patterns. For small and centrally located tumors, the system was not considered beneficial due to lack of integration into the robotic console. A fully integrated system with real-time overlays within the robotic stereo viewer was found to be the ideal scenario. Conclusion We deployed a preliminary VR-assisted surgical navigation tool for robotic-assisted radical prostatectomies.

Phospho-Akt (P-Akt1) promotes proliferation and increased survival in vitro and plays an important role in prostate cancer (PCa) progression as well as the prediction of the probability of recurrence. In this study, the goal was to demonstrate the involvement and impact of P-Akt1 on cellular interactions, biomechanisms, and pathways in PCa. Tissue microarrays from 640 PCa patients were immunostained with various antibodies. Ki-67 was used to measure proliferation index, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling was used for apoptotic index. Increased expression of P-Akt1 was associated with an increased proliferation but inversely correlated with apoptotic index. Higher levels of P-Akt1 are associated with both higher levels of cytoplasmic p27 and higher levels of nuclear p27, suggesting an involvement in both cytoplasmic entrapment and phosphorylation of p27. P-Akt1 expression significantly correlated with nuclear and cytoplasmic staining of FHKR and GSK. The strongest correlations were found with the P- forms of both, suggesting enzyme kinetics in the latter. Here, phosphorylation is the principal method of FHKR and GSK inactivation. P-Akt1 correlated with nuclear transcription factor kappa B, suggesting a role in the inhibition through phosphorylation of nuclear transcription factor kappa B. The results of the current study are unique because of the scope of the markers and the size of the population used. In vitro- and in vivo-derived information of P-Akt1 and its downstream effectors demonstrates significant involvement in PCa. Our data suggest that PCa uses multiple mechanisms to regulate this pathway and substantiate the concept of redundancy in cancer pathway regulation. Consequently, new hypothesis-driven studies can be derived from this information.

Papillary renal cell carcinoma (pRCC) is the second most common subtype of kidney cancer after clear cell renal cell carcinoma (ccRCC) and accounts for approximately 15–20% of renal malignancies [1, 2]. The term papillary RCC is a histologic designation, and the diagnosis is based on the presence of papillary or tubulopapillary structures on histopathologic evaluation. Historically, two histologic subtypes of papillary RCC, type 1 and type 2, have been recognized [3]; however, there is considerable histologic and molecular heterogeneity underlying this entity that transcends this simple histologic classification [2]. As with clear cell RCC, both sporadic and hereditary forms of pRCC have been described. In both sporadic and hereditary forms, pRCC may present with unifocal or bilateral and multifocal tumors. Hereditary forms of pRCC include hereditary papillary renal carcinoma (HPRC) and hereditary leiomyomatosis and renal cell carcinoma (HLRCC); papillary RCC has been seen infrequently in patients with other hereditary syndromes such as Birt-Hogg-Dube (BHD) [4–6]. Based on various studies, a higher incidence of sporadic pRCC is thought to occur in patients with end-stage renal disease (ESRD) and acquired renal cystic disease (ARCD) compared to the general population [7, 8]. However, the risk association of ESRD with pRCC was not seen in a more recent Japanese study of over 400 patients with dialysis-associated RCC [9].

Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics.

Identifying patients with prostate cancer (CaP) who will ultimately develop bone metastasis (BM) or die of disease is essential. Alkaline phosphatase velocity (APV) has been shown to predict overall survival (OS) and bone metastasis-free survival (BMFS) in an earlier study of an equal access military patient cohort of patients with castrate-resistant prostate cancer (CRPC). To confirm these findings, we examined a cohort of patients from a high-volume cancer center to validate a previous observation that faster alkaline phosphatase (AP) kinetics are predictive of OS and BMFS in this second cohort of patients.A retrospective cohort study was conducted of patients with CRPC treated at Memorial Sloan Kettering Cancer Center between 1989 and 2010. All patients who received androgen deprivation therapy (ADT) as primary treatment in response to a rising PSA after definitive surgery for CaP were eligible. For those who received primary ADT or surgery followed by ADT, CRPC was defined as one rising PSA value after a PSA nadir ≤4ng/ml, and confirmed by a second rising PSA value, with concurrently documented testosterone levels50ng/dl. APV was computed as the slope of the linear regression line of all AP values (2 values per patient) plotted against time. Study outcome included BMFS and OS. Univariable Kaplan-Meier analysis was used to examine time-to-event outcomes. Multivariable Cox proportional hazards regression analysis was used to model time to BMFS and OS.Of 89 patients with CRPC with evaluable data and CRPC, 17 (19%) experienced BM and 26 (29%) died. APV was dichotomized at the uppermost quartile split of all observed APV values:≥5.42U/l/y vs. the lower 3 quartiles combined,5.42U/l/y. Patients with faster APV had significantly worse outcomes, including faster progression to BM and poorer OS when compared with those with slower APV (P = 0.0451 and P = 0.0109, respectively). There was strong correlation between PSA doubling time (PSADT) (10,≥10mo) and APV (≥5.42U/l/y vs.5.42U/l/y) (P = 0.0289), preventing simultaneous evaluation of both factors in multivariable analysis. Kaplan-Meier analysis showed that PSADT was also predictive of BM and OS (log-rank P0.0001). Separate multivariable Cox proportional hazards regression models were used to examine PSADT and APV, as predictors of each study outcome (BMFS and OS). Both PSADT and APV were strongly predictive of BMFS and OS (respectively).APV and PSADT were predictors of BM and OS in patients with CRPC, respectively. These data are additional evidence of the potential value of AP kinetics in patients with advanced CaP. Prospective studies will be required to clarify these associations. However, given the restrictions on the current patient population in excluding metastatic disease within 12 months of ADT and a PSA nadir4ng/ml, the findings are not inappropriately generalized to other men.

Testicular granulosa cell tumors (GCTs) are very rare neoplasms. Although adult GCTs are thought to have a relatively indolent course, several reports have demonstrated the malignant potential of these lesions. In case of distant metastases, the overall survival is very short. To date, there is no well-established treatment for these tumors owing to poor results and very rapid progression. A 55-year-old male patient was diagnosed with a testicular GCT with distant lung metastases. He underwent surgical treatment with orchiectomy and adjuvant polychemotherapy (cisplantine, etoposide, and bleomycine) as well as metastasectomy of the right lung. We report the first case of a successfully treated testicular GCT with bipulmonary metastases at initial diagnosis. Thirty-nine months after treatment, the patient is alive with no evidence of disease. We subsequently reviewed all reported cases of an adult GCT in the published literature (25 published cases). This review will summarize all reported cases and discuss treatment options. The current case suggests that a combination of varying treatment modalities could be a promising and reasonable way to manage malignant advanced GCT of the adult testis.

e16030 Background: Heat shock protein 90 (HSP90) is a chaperone for many proteins integral development of cancer, making inhibition of HSP90 an attractive strategy for cancer treatment. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we present a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder cancer in response to HSP90 inhibition. Methods: We assessed the antitumor activity of five HSP90 inhibitors in 5637 bladder cancer cell line using MTS, cell viability, and caspase 3/7 assays. We then performed a proteomic analysis of cells before and after treatment with the HSP90 inhibitors and assessed for changes. Results: We show that the five HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells. HSP90 inhibitors also had differential effects on cell survival between bladder cancer cells and uroepithelial cells. Our proteomic study quantified 518 twofold up-regulated and 811 twofold downregulated proteins common to both AUY922 and ganetespib treatment (P < 0.05). The subsequent bioinformatic analysis revealed that those differentially expressed proteins were involved in chromatin modifications and cell death-associated pathways. Further, quantitative proteome studies identified 14 different types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells, suggesting that HSP90 inhibitors may exert multiple cytotoxic actions in bladder cancer cells by inhibiting HSP90 activity or altering the structure of chromatin. Conclusions: This study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder cancer cells, and supports the notion that HSP90 inhibitors both as single agents and in combination might provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration.

e540 Background: Magnetic resonance imaging (MRI)/transrectal ultrasound (TRUS) fusion-guided prostate biopsy (FBx) has rapidly proliferated in prostate cancer evaluation. FBx success may be dependent on multiple factors, including skills learned with user experience and the type of ultrasound (US) probe used. Our objective of this study was to compare the accuracy of the MRI/TRUS FBx technique utilizing an end fire versus a side fire US probe on an FBx platform. Methods: The participants of the study consisted of three different experience levels (expert ( > 1000 FBx), Urology fellows with none to minimal FBx experience, Urology residents with no FBx experience). Each participant performed three trials of the FBx with the UroNav System in separate phantom models of the prostate. Each trial involved targeting the same set of fiducials through FBx platform and then using US only; first using an end fire US probe, and then using a side fire US probe. Fusion registration error (FRE) was defined as the distance between MR target and transformed core location from the US only biopsy. Results: Six users with 3 different experience levels performed the FBx. Mean FRE with the end fire probe for the residents, fellows, expert was 7.42(±0.11), 5.10(±0.73) & 3.75(±0.75) respectively. Mean FRE with the side fire probe for the residents, fellows, expert was 6.08(±0.09), 4.76(±0.68) & 3.46(±0.08) respectively. There was no significant difference between the FRE averages for end fire vs. side fire. There was an inverse relationship of mean FRE with user experience level (corr. coefficient (r) = -0.79, p = 0.011 for end fire; r = -0.84, p = 0.004 for side-fire). Conclusions: We report the results of a pilot study comparing the efficacy of side fire and end fire US probes in MRI/TRUS FBx. Our preliminary results suggest the type of US probe used does not significantly affect FRE and FBx performance. As expected, FRE decreases with increased user experience. A larger study with more participants will be needed to compare these probes with adequately powered analysis and will dictate the practice in clinical settings as minimization of FRE will improve diagnostic accuracy of this technique in detecting clinically significant cancer.

A 36-year-old male with a history of cryptorchidism of the right side, treated with orchidopexy at the age of 4, presented with bilateral testicular swelling.Investigations included laboratory workup, ultrasound of both testes, as well as CT-scan of the chest, abdomen, and pelvis. Initial treatment was bilateral orchiectomy.Scrotal examination revealed a mass on the left side and a small right testis with a hard mass at the lower pole. One markedly enlarged right inguinal lymph node was palpable. LDH, betaHCG, and AFP were significantly elevated. Scrotal ultrasound revealed a homogeneous hypoechoic right testis without a mass and a heterogeneous mass containing multiple inhomogeneous cystic areas on the left side. A hypoechoic mass was visualized in the right groin. CT evaluation revealed an enlarged retroperitoneal lymph node on the left side.Histopathological evaluation revealed seminoma of the right testis, nonseminomatous germ cell tumor of the left testis, and metastatic seminoma in the right groin postoperatively.Due to improved diagnostic tools as well as the establishment of various adjuvant treatment options, the mortality of testicular cancer generally decreased in the last decades. However, metastatic bilateral testicular cancer of different histology is a challenging situation for the urologist, which warrants further discussion. Adjuvant treatment as well as postoperative follow-up should be chosen carefully.

We previously reported that reactive stroma grading in prostate cancer (PCa) is predictive of biochemical recurrence in prostatectomies and biopsies. In this study, we tested whether quantifying the percentage of reactive stromal grade 3 (RSG 3; stromogenic carcinoma pattern) in the entire tumor is predictive of PCa-specific death. Whole-mount prostatectomies operated by a single surgeon obtained between 1983 and 1998 were reviewed. Reactive stroma was evaluated as described previously, and areas of RSG 3 in the entire tumor were registered as percentages of total tumor. Statistical analysis was performed using Spearman, Kaplan-Meier, and Cox analyses. In all, 872 cases were evaluable. Quantification of RSG 3 percentage was an independent predictor of biochemical recurrence, analyzed as a continuous or grouped variable. Patients with higher RSG 3 percentages (larger tumor areas with RSG 3) had a significantly decreased biochemical recurrence-free survival than those with a lower RSG 3 percentage, even within the Gleason score 7 subset of patients. A nomogram introduced this new variable to the model. Furthermore, quantification of RSG 3 percentage was significantly predictive of PCa-specific death. Quantification of the RSG 3 (stromogenic carcinoma) area in PCa provides additional novel information on prognosis. These data substantiate the concept that the tumor microenvironment holds significant predictive information, as well as biological significance.

Introduction Urologists and pathologists have focused more and more on the anatomic structures of the human prostate gland and their relationship to prostate carcinoma development and prognosis since the resurgence of radical prostatectomy in the late 1980s. The accessibility of whole-mount slide preparation in the study of the prostate has greatly simplified this analysis. This chapter concentrates on the anatomy of the prostate gland and analyzes how anatomic structures relate to the origin, development, and evolution of prostate carcinoma. The concept of zonal anatomy and its role in prostate carcinoma will also be described. Anatomy and histology of the normal prostate gland Embryology and development of the prostate gland During the third month of gestation, the prostate gland develops from epithelial invaginations from the posterior urogenital sinus under the influence of the underlying mesenchyme [1]. The normal formation of the prostate gland requires the presence of 5α-dihydrotestosterone, which is synthesized from fetal testosterone by the action of 5α-reductase [2]. This enzyme is localized in the urogenital sinus and external genitalia of humans [3]. Consequently, deficiencies of 5α-reductase will cause a rudimentary or undetectable prostate in addition to severe abnormalities of the external genitalia, although the epididymides, vasa deferentia, and seminal vesicles remain normal [4]. During the prepubertal period, the constitution of the human prostate remains more or less identical but begins to undergo morphologic changes into the adult phenotype with the beginning of puberty.