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Purpose There remains limited data as to the feasibility, safety, and efficacy of higher doses of elective radiation therapy to the pelvic lymph nodes in men with high-risk prostate cancer. We conducted a phase II study to evaluate moderate dose escalation to the pelvic lymph nodes using a simultaneous integrated boost to the prostate. Methods and Materials Patients were eligible with biopsy-proven adenocarcinoma of the prostate, a calculated lymph node risk of at least 25%, Karnofsky performance scale ≥70, and no evidence of M1 disease. Acute and late toxicity were prospectively collected at each follow-up using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). The pelvic lymph nodes were treated to a dose of 56 Gy over 28 fractions with a simultaneous integrated boost to the prostate to a total dose of 70 Gy over 28 fractions using intensity-modulated radiation therapy. Results Thirty patients were prospectively enrolled from October 2010 to August 2014. Median patient age was 70 years (57-83), pretreatment prostate-specific antigen was 11.5 ng/mL (3.23-111.5), T stage was T2c (T1c-T3b), and Gleason score was 9 (6-9). CTCAE v4.0 rate of any grade 1 or 2 genitourinary and gastrointestinal toxicity were 55% and 44%, respectively, and there was 1 reported acute grade 3 genitourinary and gastrointestinal toxicity, both unrelated to protocol therapy. With a median follow-up of 6.4 years, the biochemical failure free survival rate was 80.2%, and mean biochemical progression free survival was 8.3 years (95% confidence interval [CI], 7.2-9.4). The prostate cancer specific survival was 95.2%, and mean prostate cancer specific survival was 8.7 years (95% CI, 8.0-9.4). Five-year distant metastases free survival was 96%. Medians were not reached. Conclusions In this single arm, small, prospective feasibility study, nodal radiation therapy dose escalation was safe, feasible, and seemingly well tolerated. Rates of progression free survival are highly encouraging in this population of predominately National Comprehensive Cancer Network very high-risk patients.

BACKGROUND Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE Prospective. POPULATION Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST Levene's test, P

BACKGROUND Accurate staging at the time of prostate cancer diagnosis is fundamental to risk stratification and management counseling. Digital rectal exam (DRE) is foundational in clinical staging of prostate cancer, even with a known limited interexaminer agreement and poor sensitivity for detecting extraprostatic disease. We sought to evaluate the prognostic value of DRE for the presence of advanced pathologic features (APFs) following radical prostatectomy (RP). METHODS All patients undergoing RP as primary treatment for clinically localized prostate cancer in the National Cancer Database between 2008 and 2014 were identified. Patients with additional malignancies, prior treatment with radiation or systemic therapy, incongruent clinical staging and DRE findings or without fully evaluable clinical staging were excluded. The primary outcome was the presence of postsurgical APFs, defined as positive surgical margins, nodal disease, or pathologic stage T3 or greater. Multivariable logistic regression analysis was performed to account for prostate-specific antigen (PSA), biopsy grade group, percent of positive biopsy cores, and clinical stage. RESULTS In total, 91,525 patients consisting of 69,182 cT1, 20,641 cT2, and 1702 cT3-T4 were included. The average age was 61.1 ± 7.0 years, and the average PSA was 8.6 ± 10.3 ng/ml. On multivariable analysis, cT3 and T4 were associated with the presence of APFs (odds ratio [OR] 11.12, p

Purpose: This study aims to combine multiparametric magnetic resonance imaging (MRI) and digitized pathology with machine learning to generate predictive maps of histologic features for prostate cancer localization. Methods and Materials: Thirty-nine patients underwent MRI prior to prostatectomy. After surgery, tissue was sliced according to MRI orientation using patient-specific 3-dimensionally printed slicing jigs. Whole-mount sections were annotated by our pathologist and digitally contoured to differentiate the lumen and epithelium. Slides were co-registered to the T2-weighted MRI scan. A learning curve was generated to determine the number of patients required for a stable machine-learning model. Patients were randomly stratified into 2 training sets and 1 test set. Two partial least-squares regression models were trained, each capable of predicting lumen and epithelium density. Predicted density values were calculated for each patient in the test dataset, mapped into the MRI space, and compared between regions confirmed as high-grade prostate cancer. Results: The learning-curve analysis showed that a stable fit was achieved with data from 10 patients. Maps indicated that regions of increased epithelium and decreased lumen density, generated from each independent model, corresponded with pathologist-annotated regions of high-grade cancer. Conclusions: We present a radio-pathomic approach to mapping prostate cancer. We find that the maps are useful for highlighting high-grade tumors. This technique may be relevant for dose-painting strategies in prostate radiation therapy. © 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)., Summary This study aims to combine whole-mount prostate pathology with multiparametric magnetic resonance imaging from 39 patients to generate predictive maps of epithelium and lumen density in magnetic resonance imaging space. We show that the new image contrasts generated stratify high-grade tumors from low-grade tumors and healthy tissue. Future studies will explore targeted radiation therapy and clinical disease staging using the radio-pathomic mapping technique.

Purpose: Prostate cancer primarily arises from the glandular epithelium. Histomophometric techniques have been used to assess the glandular epithelium in automated detection and classification pipelines; however, they are often rigid in their implementation, and their performance suffers on large datasets where variation in staining, imaging, and preparation is difficult to control. The purpose of this study is to quantify performance of a pixelwise segmentation algorithm that was trained using different combinations of weak and strong stroma, epithelium, and lumen labels in a prostate histology dataset. Approach: We have combined weakly labeled datasets generated using simple morphometric techniques and high-quality labeled datasets from human observers in prostate biopsy cores to train a convolutional neural network for use in whole mount prostate labeling pipelines. With trained networks, we characterize pixelwise segmentation of stromal, epithelium, and lumen (SEL) regions on both biopsy core and whole-mount H&E-stained tissue. Results: We provide evidence that by simply training a deep learning algorithm on weakly labeled data generated from rigid morphometric methods, we can improve the robustness of classification over the morphometric methods used to train the classifier. Conclusions: We show that not only does our approach of combining weak and strong labels for training the CNN improve qualitative SEL labeling within tissue but also the deep learning generated labels are superior for cancer classification in a higher-order algorithm over the morphometrically derived labels it was trained on.

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2–Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2–Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2–Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2–Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2–Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.

To describe the factors affecting patients' selection of a urologist, and the utilization of the Internet and social media.All new patients presenting to a single-institution for evaluation were invited to complete an anonymous 26-item questionnaire between April 2018 and October 2018, including demographic information, use of Internet and social media resources, and relative importance of factors when selecting a urologist. Descriptive statistics were reported, and a stratified analysis was performed for age, gender, and education.A total of 238 patients responded. More than half (53%) of patients searched their medical condition prior to presentation. When stratified by age, younger patients were 3 times as likely to utilize Internet resources (Group 1 vs Group 2; OR 3.3, 95%CI 1.5-7.2, P.01). Few patients utilized Facebook (7%) or Twitter (1%). The 3 most important surveyed urologist selection factors included hospital reputation (4.3 ± 1.0), in-network providers (4.0 ± 1.3), and appointment availability (3.9 ± 1.0). The 3 least important included medical school attended (2.7 ± 1.3), urologist on social media (1.9 ± 1.2), and TV, radio, and/or billboard advertisements (1.7 ± 1.3).This study suggests a significant proportion of patients search the Internet regarding their medical condition prior to presenting to clinic. Further, younger patients utilize this methodology significantly more than the senior population. Important factors when selecting a urologist may be driven by a hospital's reputation, in addition to scheduling convenience.

To evaluate contemporary trends in the management of small renal masses and how patient age has impacted practice patterns.Using the NCDB Participant User File (PUF) from 2002 to 2015, we identified patients with T1a renal masses. The initial treatment was categorized as radical nephrectomy (RN), partial nephrectomy (PN), ablation, or active surveillance (AS). A multinominal logistic regression model was used to identify significant factors impacting treatment.We identified 75,691 patients for analysis. RN, PN, and ablation accounted for 28%, 52%, and 12%, respectively, while 8% were managed with AS. In the past decade the likelihood of undergoing PN, ablation, or surveillance compared to RN has consistently increased, independent of age, sex, race, comorbidity, tumor size, or institution. As age increased, patients were independently less likely to undergo PN and more likely to be managed with ablation or AS. Compared to patients under 40 years of age, patients between 70 and 79 were far less likely to undergo PN (RR 0.58, P.01), and far more likely to undergo either ablation (RR 5.53, P.01) or AS (RR 3.7, P.01).Trends in small renal mass management continue to evolve, with PN supplanting RN over the past decade as the predominant surgical treatment. Age significantly impacts treatment selection, particularly in older cohorts whom are much more likely to undergo ablation or AS. While the use of minimally invasive therapies has increased over the past decade, AS lags behind despite quality data supporting its use. When controlling for multiple clinical factors, PN, ablation and surveillance have consistently increased in utilization compared to RN.

Prostate cancer is the most common noncutaneous cancer in men in the United States. The current paradigm for screening and diagnosis is imperfect, with relatively low specificity, high cost, and high morbidity. This study aims to generate new image contrasts by learning a distribution of unique image signatures associated with prostate cancer. In total, 48 patients were prospectively recruited for this institutional review board–approved study. Patients underwent multiparametric magnetic resonance imaging 2 weeks before surgery. Postsurgical tissues were annotated by a pathologist and aligned to the in vivo imaging. Radiomic profiles were generated by linearly combining 4 image contrasts (T2, apparent diffusion coefficient [ADC] 0-1000, ADC 50-2000, and dynamic contrast-enhanced) segmented using global thresholds. The distribution of radiomic profiles in high-grade cancer, low-grade cancer, and normal tissues was recorded, and the generated probability values were applied to a naive test set. The resulting Gleason probability maps were stable regardless of training cohort, functioned independent of prostate zone, and outperformed conventional clinical imaging (area under the curve [AUC] = 0.79). Extensive overlap was seen in the most common image signatures associated with high- and low-grade cancer, indicating that low- and high-grade tumors present similarly on conventional imaging.

Background: A significant fraction of prostate cancer patients experience post–radical prostatectomy (RP) biochemical recurrence (BCR). New predictive markers are needed for optimizing postoperative prostate cancer management. STAT5 is an oncogene in prostate cancer that undergoes amplification in 30% of prostate cancers during progression. Methods: We evaluated the significance of a positive status for nuclear STAT5 protein expression versus STAT5 locus amplification versus combined positive status for both in predicting BCR after RP in 300 patients. Results: Combined positive STAT5 status was associated with a 45% disadvantage in BCR in Kaplan–Meier survival analysis in all Gleason grade patients. Patients with Gleason grade group (GG) 2 and 3 prostate cancers and combined positive status for STAT5 had a more pronounced disadvantage of 55% to 60% at 7 years after RP in univariate analysis. In multivariate analysis, including the Cancer of the Prostate Risk Assessment Postsurgical nomogram (CAPRA-S) variables, combined positive STAT5 status was independently associated with a shorter BCR-free survival in all Gleason GG patients (HR, 2.34; P = 0.014) and in intermediate Gleason GG 2 or 3 patients (HR, 3.62; P = 0.021). The combined positive STAT5 status improved the predictive value of the CAPRA-S nomogram in both ROC-AUC analysis and in decision curve analysis for BCR. Conclusions: Combined positive status for STAT5 was independently associated with shorter disease-free survival in univariate analysis and was an independent predictor for BCR in multivariate analysis using the CAPRA-S variables in prostate cancer. Impact: Our results highlight potential for a novel precision medicine concept based on a pivotal role of STAT5 status in improving selection of prostate cancer patients who are candidates for early adjuvant interventions to reduce the risk of recurrence.

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.

Background: Prostate cancer clinical stage T2 (cT2) subclassifications, as determined by digital rectal examination (DRE), are a historic method of staging prostate cancer. However, given the potential discomfort associated with prostate examination and the wide availability of other prognostic tests, the necessity of DRE is uncertain. This study sought to determine the prognostic value of the prostate cancer cT2 subclassifications in a contemporary cohort of patients. Methods: The National Cancer Database was used to identify a cohort of men with high-risk clinical T2N0M0 prostate cancer treated with external-beam radiotherapy and androgen deprivation therapies ± surgery from 2004 to 2010. We assessed overall survival from a landmark time of 10 months using Kaplan-Meier and log-rank test analysis. A multivariate proportional hazards model was used to estimate the simultaneous effects of multiple factors, including cT2 subclassification and other well-established prognostic indicators of overall survival in prostate cancer. Results: A total of 5,291 men were included in the final analysis, with a median follow-up of 5.4 years. The cT2a, cT2b, and cT2c subclassifications demonstrated increasing hazard ratios of 1.00 (reference), 1.25 (95% CI, 1.07–1.45; P=.0046), and 1.43 (95% CI, 1.25–1.63; PConclusions: Results show that cT2 subclassifications had independent prognostic value in a large and contemporary cohort of men. cT2 classification remains an important, low-cost prognostic tool for men with prostatic adenocarcinoma. The clinical relevance of this test should be appreciated and accounted for by providers treating prostate adenocarcinoma.

Liquid biopsies, examinations of tumor components in body fluids, have shown promise for predicting clinical outcomes. To evaluate tumor-associated genomic and genetic variations in plasma cell-free DNA (cfDNA) and their associations with treatment response and overall survival, we applied whole genome and targeted sequencing to examine the plasma cfDNAs derived from 20 patients with advanced prostate cancer. Sequencing-based genomic abnormality analysis revealed locus-specific gains or losses that were common in prostate cancer, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. To estimate tumor burden in cfDNA, we developed a Plasma Genomic Abnormality (PGA) score by summing the most significant copy number variations. Cox regression analysis showed that PGA scores were significantly associated with overall survival (p < 0.04). After androgen deprivation therapy or chemotherapy, targeted sequencing showed significant mutational profile changes in genes involved in androgen biosynthesis, AR activation, DNA repair, and chemotherapy resistance. These changes may reflect the dynamic evolution of heterozygous tumor populations in response to these treatments. These results strongly support the feasibility of using non-invasive liquid biopsies as potential tools to study biological mechanisms underlying therapy-specific resistance and to predict disease progression in advanced prostate cancer.

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy. Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. Conclusions: This work introduces a novel concept of a pivotal role of Jak2–Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2–Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917–31. ©2018 AACR.

To evaluate the rate of perioperative complications after plasmakinetic bipolar and monopolar transurethral resection of bladder tumor (BTURB and MTURB). In addition, the study identifies patient and procedure characteristics associated with early complications.Retrospective review was conducted on patients undergoing transurethral resection of bladder tumor procedures at a single institution from 2003 to 2013 to assess the 30-day complication rates associated with BTURB and MTURB.Four hundred twenty-seven patients met inclusion criteria and underwent 586 procedures (379 BTURB and 207 MTURB). Baseline patient demographics, tumor stage, and tumor grade were similar in BTURB and MTURB cohorts. The overall complication rate was 34.3% for MTURB and 26.7% for BTURB. The most frequent complications were acute urinary retention (AUR) 11%, hematuria 8%, and urinary tract infection (UTI) 7%. There was no statistical difference in rates of AUR, hematuria, UTI, or readmission for continuous bladder irrigation or hemostasis procedures between BTURB and MTURB cohorts. There was a trend toward lower perforation rate during BTURB (2.6% vs 5.8%). In multivariate logistic regression analysis, MTURB, male gender, and large resections were predictive of overall complications. Male gender was associated with hematuria and AUR. Large bladder tumor resection size was also associated with increased risk of overall complications and AUR.BTURB was associated with a lower risk of overall complications, but there was no difference in the rate of hematuria in the two cohorts. Male gender and large tumor size are associated with higher risk of early complications.

Exposure of urothelial carcinoma cells to bacillus Calmette-Guérin affects cellular redox status and tumor cell biology but the mechanism(s) remain unclear. We examined free radical production by bacillus Calmette-Guérin in tumor cells in response to the bacillus using global profiling of reactive oxygen species/reactive nitrogen species. The relationship between free radical generation and downstream cellular events was evaluated.Using fluorescent probes we performed global profiling of reactive oxygen species/reactive nitrogen species in heat killed and viable bacillus Calmette-Guérin, and in the 253J and T24 urothelial carcinoma cell lines after exposure to the bacillus. Inhibition of bacillus Calmette-Guérin internalization and H2O2 pharmacological scavenging were studied for their effect on cellular reactive oxygen species/reactive nitrogen species generation and various physiological end points.Viable bacillus Calmette-Guérin produced H2O2 and O2(-) but nitric oxide was not generated. Loss of viability decreased H2O2 production by 50% compared to viable bacillus. Bacillus Calmette-Guérin internalization was necessary for the bacillus to induce reactive oxygen species/reactive nitrogen species generation in urothelial carcinoma cells. Pharmacological H2O2 scavenging reversed reactive oxygen species/reactive nitrogen species mediated signaling in urothelial carcinoma cells. Bacillus Calmette-Guérin dependent alterations in tumor biology, including intracellular signaling, gene expression and cytotoxicity, depended on free radical generation.This study demonstrates the importance of free radical generation by bacillus Calmette-Guérin and intracellular generation of cellular oxidative stress on the urothelial carcinoma cell response to the bacillus. Manipulating the cellular oxidative stress induced by bacillus Calmette-Guérin represents a potential target to increase the efficacy of the bacillus.

Objective To report the long-term oncologic outcomes of laparoscopic cryoablation for clinical stage T1 renal masses at the Medical College of Wisconsin. Materials and Methods A retrospective chart review was performed evaluating patients who underwent laparoscopic cryoablation for renal masses at the Medical College of Wisconsin between February 2000 and October 2009. Results A total of 171 renal masses in 144 patients were treated by laparoscopic cryoablation during the study period. After excluding patients with clinical stage I disease, 112 renal masses treated in 92 patients remained for analysis. Mean patient age was 59.6 years (standard deviation [SD], 12.5 years). Mean lesion size was 2.3 cm (SD, 0.94 cm). Mean age adjusted Charlson comorbidity index was 4.55 (SD, 1.69). Mean follow-up was 97.9 months (SD, 24.8 months). Overall survival among all patients was 80.9%. Lesions were biopsy proven to be malignant in 70 patients (76.3%). Of those with biopsy-proven malignancy, there were 6 recurrences, 14 non–cancer-related deaths, and 1 cancer-related death, leading to an overall survival of 77.6%, progression-free survival of 91.0%, and cancer-specific survival of 98.5%. Conclusion We report the largest published series of laparoscopic renal cryoablation with the longest follow-up. Our series indicates that laparoscopic cryoablation is both an efficacious treatment for clinical stage T1 renal masses and provides excellent long-term oncologic outcomes.

Purpose: The attenuated mycobacterium bacillus Calmette-Guerin is widely used as intravesical immunotherapy for nonmuscle invasive urothelial carcinoma. Previous studies demonstrated that in the laboratory and clinical settings bacillus Calmette-Guerin viability is a variable that correlates with antitumor efficacy. We evaluated how loss of viability impacted a number of molecular and phenotypic intermediate end points that characterize and/or contribute to the direct effect of bacillus Calmette-Guerin on urothelial carcinoma cells.Materials and Methods: We studied the effect of loss of bacillus Calmette-Guerin viability on the tumor cell response to the treatment in 2 human urothelial carcinoma cell lines. The cellular response to bacillus Calmette-Guerin rendered nonviable by heat killing was compared to the response to viable bacillus. Response end points included the induction of oxidative stress, activation of intracellular signaling pathways, gene transactivation and phenotypic changes.Results: Loss...

221 Background: Androgen targeted therapy remains the mainstay for advanced prostate cancer (PC). Second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ), re-targets persistent AR activity in castrate-resistant (CR) PC tumors, and is approved for CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients succumb to PC. Mechanisms underlying resistance to ENZ are incompletely understood. Prior work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in ENZ-resistant growth of PC. Methods: Levels of Jak2 and Stat5 activation in PC cells, tumors and patient samples were evaluated by immunohistochemistry, 3D tumor explant cultures and western blotting. Jak2 and Stat5 were inhibited by lentiviral (expression of) shRNA or pharmacologically. Levels of mRNA were assessed by QPCR and gene expression profiling. Results: ENZ induced a robust increase in Stat5 activation in PC cells in vitro, in xenograft tumors in vivo and in patient-derived PCs during ENZ treatment. Mechanistically, ENZ activation of Stat5 involves a positive feed-forward mechanism where ENZ-liganded AR induces rapid and sustained Jak2 phosphorylation in PC cells through a process involving Jak2-specific phosphatases. This results in a formation of a positive feed-forward loop in PC where activated Stat5 induces Jak2 mRNA and protein levels in PC. We showed that active Stat5 increased viability of PC cells during ENZ treatment and, at the same time, inhibition of Stat5 as a second-line treatment induced excessive death of PC cells surviving ENZ treatment. Importantly, pharmacological Stat5 blockade inhibited CR growth of PC xenograft tumors after ENZ resistance developed. Conclusions: Collectively, this work introduces a novel concept for a pivotal role of Jak2-Stat5 signaling in mediating resistance of PC to ENZ. Pharmacological Jak2-Stat5 inhibition may provide efficacious therapy in advanced PC in combination with ENZ or after ENZ fails.

BACKGROUND Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN).

Irritative voiding symptoms are to the urinary tract much as a cough is to the pulmonary system, that is, a nonspecific manifestation of multiple potential underlying causes. Key to the evaluation and management of patients with these symptoms is a clear understanding of the differential diagnosis, the diagnostic tests required for evaluation, and the role of specialists in diagnosis and treatment. This article outlines a general diagnostic approach for patients with irritative voiding symptoms. Treatment approaches for the diseases, as well as the initial management that may be performed in the primary care setting, are also discussed.

INTRODUCTION AND OBJECTIVES: The direct phenotypic effects of BCG on human urothelial carcinoma (UC) cells include cell cycle arrest, apoptotic resistance, and caspase-independent cell death. These effects are associated with increased expression of the cyclin dependant kinase inhibitor (CDKI) p21. This study assessed the role of p21 expression in mediating the phenotypic effects observed in response to BCG. METHODS: Inducible systems for the autocrine expression of p21, or the shRNA mediated blockade of p21 expression in response to BCG, were established in the human UC line T24. The effect of increasing or inhibiting p21 expression on tumor phenotype was assessed using assays for cell cycle compartmentalization (flow cytometry), apoptotic sensitivity (Caspase 3 activation), and cytotoxicity (vital dye exclusion). Results were compared to the phenotypic changes observed in response to BCG alone. RESULTS: BCG treatment alone resulted in cell cycle arrest in G0/G1, apoptotic resistance and caspase-independent cytotoxicity. p21 overexpression resulted in cell cycle arrest with a significant increase in the percentage of the cell in G0/G1 phase when compared with the untreated group (p = 0.006). p21 expression decreased basal caspase-3 expression when compared with untreated group and significantly reversed Camptothecin induced caspase-3 activity when compared with the Camptothecin alone group (p = 0.001). p21 overexpression increased BCG’s direct cytotoxicity (p = 0.0003). Inhibition of p21 expression in response to BCG failed to reverse BCG induced changes in cell cycle compartmentalization. p21 inhibition significantly reversed the antiapoptotic effect of BCG (p = 0.048). The expression of p21 was required for the direct cytotoxic effect of BCG (p = 0.004) CONCLUSIONS: p21 expression is sufficient but not necessary for BCG induced CCA. It is both sufficient and necessary for the full anti-apoptotic effect of BCG. p21 expression alone is not sufficient for caspase-independent cytotoxicity but is necessary for BCGs’ direct cytotoxic effect. These findings support a central role for p21 in mediating the phenotypic response of the tumor to BCG exposure.

Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen-deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in PC, and if Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet assay and clonogenic survival assay, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end-joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors, and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not affecting radiation sensitivity of the neighboring tissues. Conclusion: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Citation Format: Cristina Maranto, Vindhya Udhane, Ayush Dagvadorj, David T. Hoang, Lei Gu, Vitali Alexeev, Kareem Malas, Karmel Cardenas, Mateusz Koptyra, Jonathan R. Brody, Ulrich Rodeck, Carmen Bergom, Ken A. Iczkowski, Ken Jacobsohn, William See, Sara M. Schmitt, Marja T. Nevalainen. Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B073.

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To evaluate the efficacy and tolerability of bicalutamide 150 mg once-daily as immediate hormonal therapy in patients with prostate cancer or as adjuvant to radical prostatectomy or radiotherapy. PATIENTS AND METHODS In all, 8113 patients with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) were enrolled in three complementary, double-blind, placebo-controlled trials. Patients were randomized to receive standard care plus either oral bicalutamide 150 mg once-daily or oral placebo. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collated from individual trials and evaluated in a combined analysis. RESULTS Overall, at a median follow-up of 9.7 years, bicalutamide significantly improved PFS (hazard ratio 0.85, 95% confidence interval 0.79–0.91; P= 0.001). Compared with placebo there was no difference in OS (hazard ratio 1.01, P= 0.77). Patients who derived benefit from bicalutamide in terms of PFS were those with locally advanced disease, with OS significantly favouring bicalutamide in patients with locally advanced disease undergoing radiotherapy (P= 0.031). Patients with localized disease showed no clinically or statistically significant improvements in PFS; there was a survival trend in favour of placebo in patients with localized disease undergoing watchful waiting (P= 0.054). The overall tolerability of bicalutamide was consistent with previous analyses, with breast pain (73.7%) and gynaecomastia (68.8%) the most frequently reported adverse events in patients randomized to bicalutamide. CONCLUSIONS Bicalutamide 150 mg, either as monotherapy or adjuvant to standard care, improved PFS in patients with locally advanced prostate cancer, but not in patients with localized disease. A pre-planned subset analysis showed a benefit for OS in patients with locally advanced disease undergoing radiotherapy. Bicalutamide 150 mg might represent an alternative for patients with locally advanced prostate cancer considering androgen-deprivation therapy.

The mouse urothelial carcinoma cell line MB49 is widely used as an in vitro and in vivo model of urothelial carcinoma. Little comparative data exist on the molecular and phenotypic responses of this cell line relative to human cell lines. We compared the effect of bacillus Calmette-Guerin on the MB49 cell line relative to responses previously observed in the human urothelial carcinoma lines T24 (ATCC) and 253J.Molecular end points in MB49 cells after bacillus Calmette-Guerin exposure were signaling pathway activation (NF-kappaB, AP1 and C/EBP), gene expression (IL-6 and p21), HMGB1 release/responsiveness and gene expression profiling at 6 hours. Phenotypic response end points were direct cytotoxicity using dye exclusion, viability on MTT assay, apoptotic sensitivity and cell cycle compartmentalization.NF-kappaB, AP1, C/EBP, IL-6 and p21 reporter constructs were activated in MB49 cells in response to bacillus Calmette-Guerin. Gene expression profiles showed an inflammatory/immune clustering response. Bacillus Calmette-Guerin decreased cell viability and induced G1 cell cycle arrest. Treatment of MB49 cells with bacillus Calmette-Guerin induced caspase independent cell death while simultaneously decreasing sensitivity to pro-apoptotic agents. Cell death was associated with release of the necrotic cell death marker HMGB1. MB49 cells expressed HMGB1 receptors and activated intracellular NF-kappaB signaling pathways in response to bacillus Calmette-Guerin.MB49 cells show molecular and phenotypic responses to bacillus Calmette-Guerin that replicate those observed in human urothelial carcinoma lines. MB49 cells appear to be an excellent model in which to study bacillus Calmette-Guerin as an antitumor agent for urothelial carcinoma.

To report the outcomes of patients with ureteroenteric strictures after ileal conduit urinary diversion that were managed with Resonance metallic ureteral stents.Ten ureteroenteric strictures in patients with ileal conduits that were managed with metallic ureteral stenting were retrospectively identified. Charts were examined for patient age, anastomosis type, stricture cause, stricture laterality, complications, and follow-up.Nine of 10 (90%) cases resulted in distal stent migration. Mean time to stent migration was 21 days (range 3-60 d).Placement of Resonance metallic stents in patients with ileal conduits is ineffective for management of ureteroenteric strictures because of the high rate of distal migration.

OBJECTIVE To evaluate the ability of bacille-Calmette Guerin (BCG) to induce caspase-independent cell death and release the necrosis-associated chemokine high molecular group box protein 1 (HMGB1) from urothelial carcinoma (UC) cells; a correlative clinical trial determined if BCG treatment resulted in increased urinary levels of HMGB1. PATIENTS, MATERIALS AND METHODS The human UC cell lines 253 J and T24 were pretreated with apoptosis inhibitors, exposed to BCG, and cell viability and ultrastructural changes measured. HMGB1 levels were assessed in cell culture supernatant after BCG treatment. The expression/function of HMGB1 receptors on the UC cell lines was determined by reverse transcription-polymerse chain reaction and the ability of exogenous HMGB1 to activate nuclear factor (NF)-κB signalling assessed. An HMGB1 enzyme-linked immunosorbent assay was used to measure HMGB1 levels in urine obtained from BCG-treated patients. RESULTS Inhibition of apoptotic pathways failed to inhibit BCG-induced cell death in UC cells. Electron microscopy showed BCG-dependent ultrastructural changes consistent with cellular necrosis. BCG exposure resulted in a binary increase in cell culture supernatant levels of HMGB1. UCs expressed multiple HMGB1 receptors. Treatment of UCs with HMGB1 activated NF-κB. In the clinical setting, six of seven patients had increased urinary levels of HMGB1 at 24 h after BCG treatment. CONCLUSIONS BCG causes direct cytotoxicity in a subpopulation of UC cells. This cytotoxicity is caspase-independent and associated with ultrastructural changes and cellular protein release (HMGB1), characteristic of necrosis. Urinary levels of HMGB1 can be elevated in patients after BCG treatment. The expression and function of HMGB1 receptors in UC cells, coupled with the known role of HMGB1 on the host immune response, suggest a role for necrosis and HMGB1 release in the antitumour effect of BCG.

Purpose Work by our group has shown that bacillus Calmette-Guerin (BCG) induces cell cycle arrest at the G1/S interface in human transitional carcinoma cell lines. This study evaluated the effect of BCG on cell cycle regulatory proteins relevant to this effect. Materials and Methods The effect of BCG on selected cell cycle regulatory proteins, including cyclin D1, p27, and p21, was assessed in 2 human cell lines. After the identification of p21 as a candidate protein, p21 regulation was evaluated using a combination of Western, reverse transcriptase polymerase chain reaction, and promoter-reporter analysis. The immediate early versus delayed nature of p21 induction was determined. Finally, given the known potential for p21 to be regulated by both p53 dependent and independent pathways, the role of p53 in BCG induced expression of p21 was evaluated. Results BCG increased p21 expression 2-fold relative to controls as measured by Western, and promoter-reporter analysis. Inhibition of protein synthesis had no effect on p21 messenger ribonucleic acid induction in response to BCG. T24 cells contained a previously reported mutation in p53. In the p53 wild-type 253J cells, deletion of one or both p53 response elements in the p21 reporter had no effect on BCG induced reporter transactivation. Conclusions BCG up-regulates expression of p21 in human transitional cell carcinoma lines. The transactivation of p21 in response to BCG occurs through an immediate early, p53 independent pathway. The finding of increased p21, together with the observation that BCG induces cell cycle arrest at the G1/S interface, supports a role for this protein in the biologic response to BCG.

Attenuated mycobacterium bacillus Calmette-Guérin is widely used as intravesical immunotherapy of nonmuscle invasive urothelial carcinoma. Currently there are limited data on the relationship between bacillus Calmette-Guérin dose intensity and tumor response. We evaluated the dose-response relationship of bacillus Calmette-Guérin to nonmuscle invasive bladder cancer in vitro using urothelial carcinoma cell lines and in vivo using an orthotopic mouse model.Two human urothelial carcinoma cell lines were used to study the effect of bacillus Calmette-Guérin dose on the tumor cell response. Internalization, activation of signaling pathways, gene transactivation, cell viability, lactate dehydrogenase and HMGB1 release were study end points. An orthotopic tumor model was used to compare the effect of different doses on the antitumor efficacy of bacillus Calmette-Guérin.Bacillus Calmette-Guérin internalization by urothelial carcinoma cells increased as a function of time and dose with a plateau at higher doses and/or long exposure times. Intracellular signaling demonstrated a similar direct, dose dependent increase. Cytokine expression by urothelial carcinoma cells as a function of dose was variable. Some genes increased progressively but others showed a decrease at the highest dose. While nonviable cell number increased in proportion to dose, the number of cells undergoing necrotic cell death decreased at higher doses. A higher dose of bacillus Calmette-Guérin (1:200) showed a better antitumor effect than a standard dose (1:50) (p0.01).Bacillus Calmette-Guérin dose has a direct impact on urothelial carcinoma cell biology. Increased dose intensity, particularly in nonresponders, may represent a strategy to increase bacillus Calmette-Guérin treatment efficacy.

for induction of protective T cell immunity. In vivo studies have shown that TDM injection resulted in suppression of tumor growth in hepatoma and ocular squamous cell carcinoma. To date, the effect of TDM on Urothelial carcinoma (UC) cells has not been studied. The objectives of this study were to measure the cytotoxic effects of TDM on BCG sensitive and BCG resistant UC cell lines and determine its mechanism of action relative to BCG. METHODS: BCG sensitive (253J, T24) and BCG resistant (RT4) UC cell lines were used to study the effect of TDM. The biologic response to TDM was compared with the response to BCG. Response endpoints included viability, LDH release, HMGB1 release, caspase-3 activity, intracellular signaling pathways (NF-kB), gene transactivation and global profiling of reactive oxygen species(ROS) and nitrogen species (RNS). RESULTS: TDM cytotoxicity was similar in both BCG sensitive and resistant cell lines. TDM significantly decreased viability (T24, p

Applying the thermoacoustic (TA) effect to diagnostic imaging was first proposed in the 1980s. The object under test is irradiated by high-power pulses of electromagnetic energy, which heat tissue and cause thermal expansion. Outgoing TA pressure pulses are detected by ultrasound transducers and reconstructed to provide images of the object. The TA contrast mechanism is strongly dependent upon the frequency of the irradiating electromagnetic pulse. When very high frequency (VHF) electromagnetic irradiation is utilized, TA signal production is driven by ionic content. Prostatic fluids contain high levels of ionic metabolites, including citrate, zinc, calcium, and magnesium. Healthy prostate glands produce more ionic metabolites than diseased glands. VHF pulses are therefore expected to generate stronger TA signal in healthy prostate glands than in diseased glands. A benchtop system for performing ex vivo TA computed tomography with VHF energy is described and images are presented. The system utilizes irradiation pulses of 700 ns duration exceeding 20 kW power. Reconstructions frequently visualize anatomic landmarks such as the urethra and verumontanum. TA reconstructions from three freshly excised human prostate glands with little, moderate, and severe cancerous involvement are compared with histology. TA signal strength is negatively correlated with percent cancerous involvement in this small sample size. For the 45 regions of interest analyzed, a reconstruction value of 0.4 mV provides 100% sensitivity but only 29% specificity. This sample size is far too small to draw sweeping conclusions, but the results warrant a larger volume study including comparison of TA images to the gold standard, histology.

Castration therapy adjuvant to radiotherapy can significantly improve overall survival compared with radiotherapy alone in patients with locally advanced prostate cancer. Although many of the adverse effects of castration therapy are manageable, they can have a detrimental effect on quality of life. Here we evaluate the efficacy and tolerability of the non-castration-based therapy bicalutamide ('Casodex') 150 mg adjuvant to radiotherapy in patients with T1-4, M0, any n prostate cancer.The subset of patients within the early prostate cancer (EPC) program who received radiotherapy with curative intent (n = 1,370) were included in the analysis. These patients were randomized to receive oral bicalutamide 150 mg once daily (n = 699) or placebo (n = 671).The median follow-up for patients included in this analysis was 7.2 years. In patients with locally advanced disease (n = 305), bicalutamide adjuvant to radiotherapy significantly improved: progression-free survival (PFS), reducing the risk of objective progression by 44% compared with radiotherapy alone [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.40, 0.78; P0.001). Prostate-specific antigen (PSA)-PFS, reducing the risk of PSA progression by 59% compared with radiotherapy alone (HR 0.41; 95% CI 0.30, 0.55; P0.001). Overall survival, reducing the risk of death by 35% compared with radiotherapy alone (HR 0.65; 95% CI 0.44, 0.95; P = 0.03). This significant overall survival benefit for bicalutamide was driven by a lower risk of prostate cancer-related deaths (16.1 vs 24.3%, respectively). There was no significant difference in PFS or overall survival in patients with localized disease (n = 1,065).In patients with locally advanced disease, bicalutamide 150 mg adjuvant to radiotherapy demonstrates significant clinical benefits in terms of overall survival, PFS and PSA-PFS compared with radiotherapy alone. The overall survival benefit in these patients is consistent with prior studies evaluating castration-based therapies adjuvant to radiotherapy (Bolla et al. in Lancet 360:103-108, 2002; Pilepich et al. in Int J Radiat Oncol Biol Phys 61:1285-1290, 2005). In addition, the clinical benefit of bicalutamide 150 mg in locally advanced patients, but not in those with localized disease, is consistent with the overall results from the EPC program (McLeod et al. BJU Int 97:247-254, 2006). Given the quality-of-life advantages of bicalutamide relative to castration, bicalutamide 150 mg adjuvant to radiotherapy is an attractive alternative for men with locally advanced prostate cancer.

We describe the results of North American Trial 23 of the bicalutamide (Casodex) early prostate cancer program in the context of the overall early prostate cancer program findings.In Trial 23, 3,292 men with T1b-4, N0-Nx (N+ not allowed) M0 prostate cancer who had undergone radical prostatectomy or radiotherapy at 96 specialist referral centers in the United States (2,974) and Canada (318) were randomized 1:1 to 150 mg bicalutamide daily or placebo in addition to standard care for 2 years.In Trial 23 at a 7.7-year median followup there were few clinical events in the bicalutamide or standard care groups and the rates of objective progression were 15.4% and 15.3%, respectively. Mortality rates were 12.9% in the treatment group and 12.3% in the standard care group, including 11.2% and 11.0% for nonprostate cancer deaths in the absence of objective progression and 1.6% and 0.9%, respectively, for mortality due to prostate cancer. No differences in the primary end points (objective progression-free and overall survival) were seen between patients treated with bicalutamide and those treated with standard care alone. Bicalutamide (150 mg) significantly improved time to PSA progression (HR 0.80, 95% CI 0.72 to 0.90, p0.001). The tolerability profile of bicalutamide was similar to that previously described.In Trial 23 the current data suggest that early or adjuvant therapy may not benefit patients at low risk for recurrence, such as those with localized disease. The findings of Trial 23 contrast with the results in the overall early prostate cancer program and in other published literature, in which bicalutamide has been shown to provide significant clinical benefit for locally advanced disease.

The prostate specific antigen level at which to recommend a bone scan after treatment of early prostate cancer is controversial. We identified the incidence of bone metastases at varying prostate specific antigen levels in asymptomatic men following radical prostatectomy, radiation therapy and watchful waiting.Data were obtained from the Early Prostate Cancer trial comparing placebo with bicalutamide in addition to standard care for localized prostate cancer. As part of the trial patients were required to have routine bone scans regardless of prostate specific antigen levels. The prostate specific antigen levels were divided into subgroups and the incidence of positive bone scans was calculated for each group.The incidence of positive bone scans in patients treated with watchful waiting and given bicalutamide or placebo was low (0.7% to 3.2%) at prostate specific antigen levels less than 20 ng/ml. At greater than this level the sample sizes were smaller but there was a significant increase in the incidence of positive bone scans. In the groups treated with radiation therapy or radical prostatectomy, regardless of the addition of bicalutamide, the incidence of positive bone scans was low (0.2% to 1.4%) at prostate specific antigen levels less than 5 ng/ml. The sample sizes were smaller at prostate specific antigen levels greater than 5 ng/ml so the results are harder to interpret.Bone scans can be confidently eliminated in the followup of patients with early prostate cancer after standard care of those with prostate specific antigen levels less than 5 ng/ml. This level can be increased to 20 ng/ml with caution in those patients treated with watchful waiting.

Purpose: We report our experience with LC for small renal tumors.Materials and Methods: Patients who underwent LC at our institution between February 2000 and September 2004 were included in the study. A retrospective chart review was done for perioperative and postoperative parameters as well as clinical outcomes.Results: A total of 65 LCs were performed in 59 patients during the period reviewed. Overall 81 renal tumors were cryoablated. Median patient age was 62 years. Median tumor size was 2.5 cm. Median operative time was 190 minutes. Median estimated blood loss was 50 ml. Median hospital stay was 2 days. Conversion to open surgery occurred in 2 patients. Nephrectomy for bleeding occurred in 1 patient. Median followup was 26.8 months. Two recurrences were identified after LC.Conclusions: LC is an alterative modality to laparoscopic partial nephrectomy or open partial nephrectomy for small renal tumors. Tumor recurrence rates in the studies published to date are comparable to those of partial nephrecto...

The role of eicosanoids (metabolites of arachidonic acid) in prostate diseases is receiving increased attention. We investigated the relationship between the concentrations of urinary free acids of 12- and 20-hydroxyeicosatetraenoic acids (12- and 20-HETE) and the benign prostatic hypertrophy (BPH) and prostate cancer (Pca). Urinary concentrations of 12-HETE and 20-HETE of BPH and Pca patients were significantly higher than normal subjects. After removal of the prostate gland, the urinary concentrations of these eicosanoids decreased to concentrations similar to the normal subjects. These results suggest that urinary free acids of 12-HETE and 20-HETE indicate an abnormality of the prostate gland.

Introduction and Objectives Prior studies have shown that bladder trauma occurring during transurethral bladder tumor resection increases urinary levels of the cytokine transforming growth factor (TGF)-β1. This study used complementary deoxyribonucleic acid micro-array technology to identify additional genes in human transitional cell carcinoma (TCC), whose expression is altered as a consequence of increased urinary levels of TGF-β1. Methods The human TCC line 253J was cultured in standard media, or media spiked with either 10% post-transurethral bladder tumor resection urine (PTU), or PTU and anti-TGF-β1 neutralizing antibody. Messenger ribonucleic acid from these conditions, together with messenger ribonucleic acid from stably transfected 253J cells over-expressing TGF-β1, was hybridized with ATLAS® micro-array membranes (Clontech, Palo Alto, CA) containing 588 human genes. Hybridization signal intensity was quantified using phospho-imaging. An analytic strategy based on the variance in the signal intensity ratio of specific housekeeping genes in control and experimental comparisons was used to identify significant changes in gene expression. Reverse transcriptase polymerase chain reaction of target genes was used to confirm gene over-expression and TGF-β1 responsiveness. Results Seven genes were identified on micro-array: v-RAF-1, colony stimulating factor-1 receptor, v-FGR, insulin growth factor-1 receptor, epidermal growth factor receptor, α5 integrin, and interferon receptor-1. Reverse transcriptase polymerase chain reaction confirmed over-expression in the autocrine TGF-β1 producing cell line and increased expression in response to exogenous TGF-β1. Conclusions TGF-β1 in PTU alters the expression of multiple genes in human TCC in vitro. The impact of these changes on the biologic phenotype of the malignant cell and the efficacy of adjuvant therapies requires further evaluation.

Background and purpose The ongoing Early Prostate Cancer (EPC) programme is assessing bicalutamide (‘Casodex') 150mg, either alone or as adjuvant to treatment of curative intent, in patients with localised or locally advanced prostate cancer ( n =8113). This paper presents an exploratory analysis of the subgroup of the EPC programme who received radiotherapy with curative intent ( n =1370) in order to determine the efficacy (in terms of progression-free survival [PFS]) and tolerability of bicalutamide 150mg in this setting. Patients and methods 1370 patients with T1-4, M0, any N prostate cancer received bicalutamide 150mg or placebo adjuvant to radiotherapy of curative intent. This analysis was undertaken at median 5.3 years' follow-up. Results In patients with locally advanced disease ( n =305), bicalutamide adjuvant to radiotherapy significantly increased PFS by 53% (event-time ratio 1.53; 95% confidence intervals [CI] 1.16, 2.02) compared with placebo and reduced the risk of disease progression by 42% (hazard ratio [HR] 0.58; 95% CI 0.41, 0.84; P =0.00348). In these patients, objective progression was experienced by 33.5% of those randomised to bicalutamide versus 48.6% for those randomised to placebo. The between-group difference in patients with localised disease ( n =1065) failed to reach statistical significance (HR 0.80; 95% CI 0.62, 1.03; P =0.088). The most common adverse events were breast pain (74.8%) and gynaecomastia (66.6%), which were mild to moderate in >90% of cases. Conclusions Bicalutamide 150mg/day given as adjuvant to radiotherapy significantly improved PFS in patients with locally advanced prostate cancer. For patients with localised disease, the results at this stage from the radiotherapy subgroup and the overall EPC programme suggest that adjuvant hormonal therapy is currently not appropriate. There were no unexpected tolerability findings.

The purpose of this study was to determine if 3D-rendered CT urography (CTU) depicts both normal and abnormal findings in patients with urinary diversions and if the addition of contrast-enhanced CT digital radiography (CTDR) improves opacification of the urinary collecting system.Thirty CTU and contrast-enhanced CTDR examinations were performed in 24 patients who underwent cystectomy for bladder cancer. Indications for evaluation included hematuria, tumor surveillance, or suspected diversion malfunction. All examinations were evaluated without knowledge of the stage or grade of a patient's tumor and were compared with the clinical records. Opacification of the urinary collecting system was evaluated with 3D CTU alone, contrast-enhanced CTDR alone, and combined CTU and CTDR.Nine abnormalities were identified including distal ureteral strictures (n = 4), vascular compression of the mid left ureter (n = 1), scarring of the mid right pole infundibulum (n = 1), bilateral hydronephrosis and hydroureter (n = 1), urinary reservoir calculus (n = 1), and tumor recurrence invading the afferent limb of the neobladder (n = 1). Eight of the nine detected abnormalities were surgically or pathologically confirmed. All abnormalities were identified on all three imaging techniques but were best seen on 3D CTU and enhanced CTDR images. Incomplete opacification of the urinary collecting system occurred in 17 patients with CTU alone, 12 patients with contrast-enhanced CTDR alone, and nine patients with combined CTU and contrast-enhanced CTDR. Compared with CTU alone, the combined technique of 3D CTU and contrast-enhanced CTDR improved opacification by a statistically significant difference (p = 0.037).CTU with 3D rendering can accurately depict both normal and abnormal postoperative findings in patients with urinary diversions. Adding enhanced CTDR can improve visualization of the urinary collecting system.

BACKGROUND The regimens of carboplatin plus paclitaxel (CP) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) were compared in patients with advanced urothelial carcinoma. METHODS Patients with metastatic urothelial carcinoma were randomized to receive either CP (paclitaxel at a dose of 225 mg/m2 and carboplatin [targeted area under the concentration-time curve (AUC) of 6] given every 21 days) or the standard M-VAC dosage. RESULTS Eighty-five patients were randomized to the respective treatment regimens (41 to CP and 44 to M-VAC). Response rates and overall survival were similar for both treatment arms. Patients treated with CP had an overall response rate of 28.2% (95% binomial confidence interval, 15.0–44.9%) compared with an overall response rate of 35.9% for the M-VAC arm (95% binomial confidence interval, 21.2–52.8%) (P = 0.63, Fisher exact test). The median progression-free survival among patients who were treated with M-VAC was 8.7 months and was 5.2 months for patients receiving CP (P = 0.24, log-rank test). At a median follow-up of 32.5 months, the median survival for patients treated with M-VAC was 15.4 months versus 13.8 months for patients treated with CP (P = 0.65, log-rank test). Patients treated with M-VAC were found to have more severe worst-degree toxicities compared with patients treated with CP (P = 0.0001). There were no significant differences with regard to quality of life as assessed by the Functional Assessment of Cancer Therapy–Bladder (FACT-BL) instrument (P = 0.33). CONCLUSIONS Interpretation of the results of this study must be made with caution because the study failed to reach its accrual goal. Patients treated with CP had a median survival of 13.8 months compared with 15.4 months for patients treated with M-VAC. Patients treated with CP appeared in general to better tolerate their treatment; however, there were no significant differences noted with regard to measured quality of life parameters. Cancer 2004. © 2004 American Cancer Society.

Autocrine expression of interleukin (IL)-6 by transitional cell carcinoma (TCC) in response to bacillus Calmette-Guerin (BCG) may have an important role in promoting BCG adherence to TCC and consequently in BCG treatment efficacy. IL-6 expression in response to BCG requires nuclear factor (NF)-kappaB mediated signal transduction. We evaluated the influence of androgens on BCG induced, NF-kappaB mediated IL-6 expression.Reverse transcriptase-polymerase chain reaction was used to confirm androgen receptor expression in the human TCC lines 253J and T24. A reporter construct containing an androgen response element was used to establish the integrity of androgen mediated signal transduction. Subsequently the dose dependent effect of dihydrotestosterone (DHT) on BCG induced IL-6 expression and NF-kappaB signaling was evaluated. Two pharmacological androgen receptor blockers were used to determine if receptor blockade inhibited the effect of DHT on activation of the androgen response element, NF-kappaB signaling and BCG induced IL-6 expression.The 2 human TCC lines expressed androgen receptor and demonstrated intact androgen stimulated signaling pathways. DHT suppressed BCG induced, NF-kappaB mediated signaling and IL-6 expression in a dose dependent manner. DHT decreased mRNA levels of IL-6, expression of the full-length IL-6 promoter construct and expression of an NF-kappaB specific reporter construct in response to BCG relative to controls. Competitive pharmacological blockade of androgen receptor inhibited the effect of DHT on BCG induced signaling in dose dependent fashion.DHT down-regulates NF-kappaB mediated IL-6 expression by human TCC lines in response to BCG. This effect depends on a functional androgen receptor signaling pathway and it can be blocked by the inhibition of androgen/androgen receptor binding.

Objective: To present management options for gynaecomastia and mastodynia associated with nonsteroidal antiandrogen therapy, supported by relevant data and case studies.

The Early Prostate Cancer (EPC) Programme was designed to evaluate the efficacy and tolerability of bicalutamide (‘Casodex') 150mg in addition to standard care (radical prostatectomy, radiotherapy, or watchful waiting) in patients with early stage prostate cancer. A total of 8113 men with localised or locally advanced prostate cancer and negative bone scans were recruited. Patients were randomised to receive either bicalutamide 150mg per day ( n =4052) or placebo ( n =4061) once daily, in addition to standard care. The primary endpoints for the programme are time to objectively confirmed progression and overall survival. Secondary endpoints include time to doubling of prostate-specific antigen (PSA) and tolerability. The tolerability profile of bicalutamide 150mg was closely related to its pharmacology, with gynaecomastia (66%) and breast pain (73%) the most frequently reported adverse events. The majority of the gynaecomastia (70%) and breast pain (90%) events improved or resolved following withdrawal from therapy. Bicalutamide 150mg significantly reduced the risk of objective progression by 42% ( p ⪡0.0001) compared with standard care alone. This effect was seen in patients with localised disease (28% reduction; p p p ⪡0.0001), and the incidence of bone metastases by 33% ( p p =0.43); however, both progression and survival continue to be followed in these ongoing studies. In conclusion, immediate bicalutamide 150mg treatment, either alone or as an adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localised or locally advanced prostate cancer.

Traditionally, clinicians have used prognostic factors such as disease stage, tumour grade, nodal status and pre-treatment prostate-specific antigen (PSA) level to stratify patients for risk of disease recurrence after primary therapy. More recently, evidence from a number of studies indicates that PSA doubling time (PSADT) subsequent to biochemical failure may also be useful in predicting clinical progression. Men with a short PSADT (