Prostate Cancer The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Evaluating the Impact of PSA as a Selection Criteria for Nerve Sparing Radical Prostatectomy in a Screened Cohort Wed, 16 Apr 2014 09:34:36 +0000 Purpose. We investigated whether NS-RP increased risk of PSA failure and whether PSA should be included as a selection criterion for NS. Methods. We evaluated 357 consecutive men with screen-detected PC who underwent open RP without adjuvant radiotherapy between 9/11/2001 and 12/30/2008. Criteria for NS included Gleason score ≤3 + 4, percentage of positive biopsies (PPB) ≤50%, percentage of core involvement ≤50%, nonapical location, no perineural invasion, and no palpable disease on pre- or intraoperative exam but did not include a PSA threshold. Cox multivariable regression assessed whether increasing PSA or unilateral- or bilateral-NS versus non-NS-RP was associated with PSA failure adjusting for prognostic factors. Results. After a median follow-up of 3.96 years, 34 men sustained PSA failure (9.5%). Increasing PSA was significantly associated with increased risk of PSA failure in the interaction model (adjusted hazard ratio (AHR): 1.09 [95% CI: 1.03–1.16]; ), whereas unilateral (AHR: 1.24 [95% CI: 0.36–4.34]; ) or bilateral NS (AHR: 0.41 [95% CI: 0.06–2.59]; ) versus non-NS RP was not. Conclusion. NS-RP in a screened cohort did not increase risk of PSA failure using NS criteria not including PSA. Shyam K. Tanguturi, Ming-Hui Chen, Marian Loffredo, Jerome P. Richie, and Anthony V. D’Amico Copyright © 2014 Shyam K. Tanguturi et al. All rights reserved. Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in Tumor-Bearing Mice Mon, 07 Apr 2014 13:57:24 +0000 Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections. Joy L. Kovar, Lael L. Cheung, Melanie A. Simpson, and D. Michael Olive Copyright © 2014 Joy L. Kovar et al. All rights reserved. Burden of Illness in Prostate Cancer Patients with a Low-to-Moderate Risk of Progression: A One-Year, Pan-European Observational Study Thu, 13 Mar 2014 09:58:14 +0000 Objective. To assess the impact of low-to-moderate risk prostate cancer on patients’ quality of life (QoL) at diagnosis and within the first year of treatment. Subjects and Methods. Men () aged 50–75 years with prostate cancer (Gleason score , PSA  ng/mL and clinical staging T1c–T2b) were enrolled in five European countries. Patients completed five questionnaires, including EORTC Quality of Life Questionnaire—Prostate Cancer 25 (QLQ-PR25) and EORTC Quality of Life Questionnaire—Cancer 30 (QLQ-C30). Questionnaires were completed at baseline, at 3 months and 12 months after starting treatment. The primary endpoint was the change in QLQ-PR25 urinary symptoms subscale score from baseline to the assessment at 3 months. Results. Mean (SD) age was 65.0 (5.7) years and 400 (66%) men had Gleason score ≤6 prostate cancer. The most frequently used initial treatment was radical prostatectomy (71% of patients). QLQ-PR25 urinary symptoms subscale score was significantly increased at 3 months (), indicating that urinary symptoms worsened after treatment. The score was lower at 12 months than at 3 months, but it was still significantly higher than at baseline (). Hormonal treatment-related symptoms, sexual functioning, and sexual activity scores significantly worsened at 3 and 12 months (all ). For the QLQ-C30 questionnaire, global health status/QoL score significantly decreased at month 3 but was not different from baseline by month 12. Scales for physical, role, and social functioning, and fatigue, showed significant deterioration at 3 and 12 months. Conclusions. Low-to-moderate risk prostate cancer may have a substantial effect on patients’ QoL within one year following treatment. Cesare Selli, Anders Bjartell, Javier Burgos, Matthew Somerville, Juan-Manuel Palacios, Laure Benjamin, Libby Black, and Ramiro Castro Copyright © 2014 Cesare Selli et al. All rights reserved. Does Statin or ASA Affect Survival When Prostate Cancer Is Treated with External Beam Radiation Therapy? Mon, 03 Mar 2014 10:08:40 +0000 Background. Prior studies evaluating the effect of statins or acetylsalicylic acid (ASA) on the survival of men receiving prostate cancer were treatment have reported conflicting results, and have not adjusted for comorbidity. Our aim is to investigate the influence of statins and ASA on prostate cancer survival, when comorbidity is adjusted for, in men treated with external beam radiation therapy (EBRT) for prostate cancer. Methods. A cohort of 3851 patients with prostate cancer treated with curative EBRT ± androgen deprivation therapy (ADT) between 2000 and 2007. Stage, treatment, medication use, and Charlson comorbidity index (CCI) scores were analyzed. Results. Median followup was 8.4 years. Mean age was 70.3 years. Neoadjuvant ADT was used in 67%. Statins were used in 23%, ASA in 24%, and both in 11%. Comorbidity scores were 0 in 65%, 1 in 25%, and ≥2 in 10% of patients. Statin and ASA use were associated with increased age and comorbidity. Although statin and ASA use were significantly associated with improved prostate cancer specific survival (PCSS) on univariate analysis, neither were on multivariate analysis. Conclusion. Neither statin nor ASA use impacted PCSS on multivariate competing risks analysis. Survival was impacted by increased comorbidity as well as statin and ASA use. J. Caon, M. Paquette, J. Hamm, and T. Pickles Copyright © 2014 J. Caon et al. All rights reserved. Natural History of Untreated Prostate Specific Antigen Radiorecurrent Prostate Cancer in Men with Favorable Prognostic Indicators Thu, 20 Feb 2014 09:39:45 +0000 Background and Purpose. Life expectancy data could identify men with favorable post-radiation prostate-specific antigen (PSA) failure kinetics unlikely to require androgen deprivation therapy (ADT). Materials and Methods. Of 206 men with unfavorable-risk prostate cancer in a randomized trial of radiation versus radiation and ADT, 53 experienced a PSA failure and were followed without salvage ADT. Comorbidity, age and established prognostic factors were assessed for relationship to death using Cox regression analyses. Results. The median age at failure, interval to PSA failure, and PSA doubling time were 76.6 years (interquartile range [IQR]: 71.8–79.3), 49.1 months (IQR: 37.7–87.4), and 25 months (IQR: 13.1–42.8), respectively. After a median follow up of 4.0 years following PSA failure, 45% of men had died, none from prostate cancer and no one had developed metastases. Both increasing age at PSA failure (HR: 1.14; 95% CI: 1.03–1.25; ) and the presence of moderate to severe comorbidity (HR: 12.5; 95% CI: 3.81–41.0; ) were significantly associated with an increased risk of death. Conclusions. Men over the age of 76 with significant comorbidity and a PSA doubling time >2 years following post-radiation PSA failure appear to be good candidates for observation without ADT intervention. Neil E. Martin, Ming-Hui Chen, Clair J. Beard, Paul L. Nguyen, Marian J. Loffredo, Andrew A. Renshaw, Philip W. Kantoff, and Anthony V. D’Amico Copyright © 2014 Neil E. Martin et al. All rights reserved. Cryotherapy for Primary Treatment of Prostate Cancer: Intermediate Term Results of a Prospective Study from a Single Institution Thu, 20 Feb 2014 07:25:49 +0000 Purpose. Published data about cryotherapy for prostate cancer (PC) treatment are based on case series with a lack of clinical trials and the inexistence of a validated definition of biochemical failure. A prospective study with standardized followup protocol was conducted in our institution. Material and Methods. Prospective study of a series of cases including 108 patients diagnosed with localized PC at clinical stage T1c-T2c treated by primary cryoablation and median followup of 61 months. Criteria of biochemical recurrence were unified according to the American Society for Therapeutic Radiology and Oncology (ASTRO). End points were biochemical progression-free survival (BPFS), cancer-specific survival, and overall survival. Rate of complications was reported. Results. The BPFS for low-, medium-, and high-risk patients was 96.4%, 91.2%, and 62.2%, respectively. Cancer-specific survival was 98.1%. Overall survival reached 94.4%. Complications included incontinence in 5.6%, urinary tract obstruction in 1.9%, urethral sloughing in 5.6%, haematuria in 1.9%, perineal pain in 11.1%, and prostatorectal fistula in 0.9%. Erectile disfunction was found in 98.1%. Conclusions. Cryotherapy is an effective and minimally invasive treatment for primary PC in well-selected cases, with low surgical risk and good results in terms of BPFS, cancer-specific survival, and overall survival. S. Alvarez Rodríguez, F. Arias Fúnez, C. Bueno Bravo, R. Rodríguez-Patrón Rodríguez, E. Sanz Mayayo, V. Hevia Palacios, and F. J. Burgos Revilla Copyright © 2014 S. Alvarez Rodríguez et al. All rights reserved. DWI of Prostate Cancer: Optimal -Value in Clinical Practice Tue, 18 Feb 2014 00:00:00 +0000 Aim. To compare the diagnostic performance of diffusion weighted imaging (DWI) using -values of 1000 s/mm2 and 2000 s/mm2 at 3 Tesla (T) for the evaluation of clinically significant prostate cancer. Matherials and Methods. Seventy-eight prostate cancer patients underwent a 3T MRI scan followed by radical prostatectomy. DWI was performed using -values of 0, 1000, and 2000 s/mm2 and qualitatively analysed by two radiologists. ADC maps were obtained at -values of 1000 and 2000 s/mm2 and quantitatively analyzed in consensus. Results. For diagnosis of 78 prostate cancers the accuracy of DWI for the young reader was significantly greater at = 2000 s/mm2 for the peripheral zone (PZ) but not for the transitional zone (TZ). For the experienced reader, DWI did not show significant differences in accuracy between -values of 1000 and 2000 s/mm2. The quantitative analysis in the PZ and TZ was substantially superimposable between the two -values, albeit with a higher accuracy with a -value of 2000 s/mm2. Conclusions. With a -value of 2000 s/mm2 at 3T both readers differentiated clinical significant cancer from benign tissue; higher -values can be helpful for the less experienced readers. Guglielmo Manenti, Marco Nezzo, Fabrizio Chegai, Erald Vasili, Elena Bonanno, and Giovanni Simonetti Copyright © 2014 Guglielmo Manenti et al. All rights reserved. Evidence Suggesting That Obesity Prevention Measures May Improve Prostate Cancer Outcomes Using Data from a Prospective Randomized Trial Thu, 13 Feb 2014 13:48:51 +0000 Purpose. Increasing body mass index (BMI) is associated with higher risk prostate cancer (PC) at presentation. Whether increasing BMI also prompts earlier salvage androgen suppression therapy (sAST) is unknown. Materials and Methods. Between 1995 and 2001, 206 men with unfavorable risk PC were treated with radiation therapy (RT) or RT and six months of androgen suppression therapy in a randomized controlled trial (RCT). 108 sustained PSA failure; 51 received sAST for PSA approaching 10 ng/mL; 49 with BMI data comprised the study cohort. A multivariable Cox regression analysis identified pretreatment factors associated with earlier sAST receipt. Results. Increasing BMI prompted earlier sAST (median years: 3.7 for overweight/obese, 6.9 for normal weight; adjusted hazard ratio (AHR): 1.11; 95% CI: 1.04, 1.18; ) as did high versus other risk PC (median: 3.2 versus 5.2 years; AHR: 2.01; 95% CI: 1.05, 3.83; ). Increasing median time to sAST was observed for overweight/obese men with high versus other risk PC and for normal-weight men with any risk PC being 2.3, 4.6, and 6.9 years, respectively ( for trend). Conclusion. Increasing BMI was associated with earlier sAST. A RCT evaluating whether BMI reduction delays or eliminates need for sAST is warranted. Ravi A. Chandra, Ming-Hui Chen, Danjie Zhang, Marian Loffredo, and Anthony V. D’Amico Copyright © 2014 Ravi A. Chandra et al. All rights reserved. Primary Zonal High Intensity Focused Ultrasound for Prostate Cancer: Results of a Prospective Phase IIa Feasibility Study Thu, 23 Jan 2014 16:31:53 +0000 Aims. In this study we report our results with storage of cryopreserved semen intended for preservation and subsequent infertility treatment in men with testicular cancer during the last 18 years. Methods. Cryopreserved semen of 523 men with testicular cancer was collected between October 1995 and the end of December 2012. Semen of 34 men (6.5%) was used for fertilization of their partners. They underwent 57 treatment cycles with cryopreserved, fresh, and/or donor sperm. Results. A total of 557 men have decided to freeze their semen before cancer treatment. Seminoma was diagnosed in 283 men (54.1%) and nonseminomatous germ cell tumors in 240 men (45.9%). 34 patients who returned for infertility treatment underwent 46 treatment cycles with cryopreserved sperm. Totally 16 pregnancies were achieved, that is, 34.8% pregnancy rate. Conclusion. The testicular cancer survivors have a good chance of fathering a child by using sperm cryopreserved prior to the oncology treatment, even when it contains only limited number of spermatozoa. Roland Van Velthoven, Fouad Aoun, Ksenija Limani, Krishna Narahari, Marc Lemort, and Alexandre Peltier Copyright © 2014 Roland Van Velthoven et al. All rights reserved. The Role of Vascular Endothelial Growth Factor in Metastatic Prostate Cancer to the Skeleton Thu, 12 Dec 2013 11:27:53 +0000 Despite the clinical implication and high incidence of bone and spinal metastases, the molecular mechanisms behind prostate cancer metastasis to bone and spine are not well understood. In this review the molecular mechanisms that may contribute to the highly metastatic phenotype of prostate cancer are discussed. Proangiogenic factors such as vascular endothelial growth factor (VEGF) have been shown to not only aid in the metastatic capabilities of prostate cancer but also encourage the colonization and growth of prostate tumour cells in the skeleton. The importance of VEGF in the complex process of prostate cancer dissemination to the skeleton is discussed, including its role in the development of the bone premetastatic niche, metastatic tumour cell recognition of bone, and bone remodeling. The expression of VEGF has also been shown to be upregulated in prostate cancer and is associated with clinical stage, Gleason score, tumour stage, progression, metastasis, and survival. Due to the multifaceted effect VEGF has on tumour angiogenesis, tumour cell proliferation, and bone destruction, therapies targeting the VEGF pathways have shown promising clinical application and are being investigated in clinical trials. Emma Roberts, Davina A. F. Cossigny, and Gerald M. Y. Quan Copyright © 2013 Emma Roberts et al. All rights reserved. Variation in HNF1B and Obesity May Influence Prostate Cancer Risk in African American Men: A Pilot Study Mon, 09 Dec 2013 16:27:31 +0000 Background. Prostate cancer (PCa) racial disparity is multifactorial, involving biological, sociocultural, and lifestyle determinants. We investigated the association between selected potentially functional polymorphisms (SNPs) and prostate cancer (PCa) risk in Black (AAM) and White (EAM) men. We further explored if these associations varied by the body mass index (BMI) and height. Methods. Age-matched DNA samples from 259 AAM and 269 EAM were genotyped for 10 candidate SNPs in 7 genes using the TaqMan allelic differentiation analysis. The dominant, recessive, and additive age-adjusted unconditional logistic regression models were fitted. Results. Three SNPs showed statistically significant associations with PCa risk: in AAM, HNF1B rs7501939 (, ) and rs4430796 (, ); in EAM, CTBP2 rs4962416 (, ). In addition, high BMI in AAM (, ) and height in EAM (, ) showed significant associations. Interestingly, HNF1B rs7501939 was associated with PCa exclusively in obese AAM (, ). Conclusion. Our results suggest that variation in the HNF1B may influence PCa risk in obese AAM. Ganna Chornokur, Ernest K. Amankwah, Stacy N. Davis, Catherine M. Phelan, Jong Y. Park, Julio Pow-Sang, and Nagi B. Kumar Copyright © 2013 Ganna Chornokur et al. All rights reserved. 3D versus 2D Systematic Transrectal Ultrasound-Guided Prostate Biopsy: Higher Cancer Detection Rate in Clinical Practice Sun, 17 Nov 2013 09:00:15 +0000 Objectives. To compare prostate cancer detection rates of extended 2D versus 3D biopsies and to further assess the clinical impact of this method in day-to-day practice. Methods. We analyzed the data of a cohort of 220 consecutive patients with no prior history of prostate cancer who underwent an initial prostate biopsy in daily practice due to an abnormal PSA and/or DRE using, respectively, the classical 2D and the new 3D systems. All the biopsies were done by a single experienced operator using the same standardized protocol. Results. There was no significant difference in terms of age, total PSA, or prostate volume between the two groups. However, cancer detection rate was significantly higher using the 3D versus the 2D system, 50% versus 34% (). There was no statistically significant difference while comparing the 2 groups in term of nonsignificant cancer detection. Conclusion. There is reasonable evidence demonstrating the superiority of the 3D-guided biopsies in detecting prostate cancers that would have been missed using the 2D extended protocol. Alexandre Peltier, Fouad Aoun, Fouad El-Khoury, Eric Hawaux, Ksenija Limani, Krishna Narahari, Nicolas Sirtaine, and Roland van Velthoven Copyright © 2013 Alexandre Peltier et al. All rights reserved. Advances in Robotic-Assisted Radical Prostatectomy over Time Tue, 12 Nov 2013 09:54:37 +0000 Since the introduction of robot-assisted radical prostatectomy (RALP), robotics has become increasingly more commonplace in the armamentarium of the urologic surgeon. Robotic utilization has exploded across surgical disciplines well beyond the fields of urology and prostate surgery. The literature detailing technical steps, comparison of large surgical series, and even robotically focused randomized control trials are available for review. RALP, the first robot-assisted surgical procedure to achieve widespread use, has recently become the primary approach for the surgical management of localized prostate cancer. As a result, surgeons are constantly trying to refine and improve upon current technical aspects of the operation. Recent areas of published modifications include bladder neck anastomosis and reconstruction, bladder drainage, nerve sparing approaches and techniques, and perioperative and postoperative management including penile rehabilitation. In this review, we summarize recent advances in perioperative management and surgical technique for RALP. Emma F. P. Jacobs, Ronald Boris, and Timothy A. Masterson Copyright © 2013 Emma F. P. Jacobs et al. All rights reserved. Quantifying the Ki-67 Heterogeneity Profile in Prostate Cancer Thu, 03 Oct 2013 15:20:35 +0000 Background: Ki-67 is a robust predictive/prognostic marker in prostate cancer; however, tumor heterogeneity in prostate biopsy samples is not well studied. Methods: Using an MRI/US fusion device, biopsy cores were obtained systematically and by targeting when indicated by MRI. Prostate cores containing cancer from 77 consecutive men were analyzed. The highest Ki-67 was used to determine interprostatic variation. Ki-67 range (highest minus lowest) was used to determine intraprostatic and intralesion variation. Apparent diffusion coefficient (ADC) values were evaluated in relation to Ki-67. Results: Interprostatic Ki-67 mean ± standard deviation (SD) values for NCCN low (L), intermediate (I), and high (H) risk patients were 5.1 ± 3.8%, 7.4 ± 6.8%, and 12.0 ± 12.4% (ANOVA ). Intraprostatic mean ± SD Ki-67 ranges in L, I, and H risk patients were 2.6 ± 3.6%, 5.3 ± 6.8%, and 10.9 ± 12.3% (ANOVA ). Intralesion mean ± SD Ki-67 ranges in L, I, and H risk patients were 1.1 ± 0.9%, 5.2 ± 7.9%, and 8.1 ± 10.8% (ANOVA ). ADC values at Ki-67 > and <7.1% were 860 ± 203 and 1036 ± 217, respectively (). Conclusions: High risk patients have significantly higher inter- and intraprostatic Ki-67 heterogeneity. This needs to be considered when utilizing Ki-67 clinically. Shane Mesko, Patrick Kupelian, D. Jeffrey Demanes, Jaoti Huang, Pin-Chieh Wang, and Mitchell Kamrava Copyright © 2013 Shane Mesko et al. All rights reserved. Galectins as New Prognostic Markers and Potential Therapeutic Targets for Advanced Prostate Cancers Tue, 24 Sep 2013 10:40:26 +0000 A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the “galectin-signature” might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa. Diego J. Laderach, Lucas Gentilini, Felipe M. Jaworski, and Daniel Compagno Copyright © 2013 Diego J. Laderach et al. All rights reserved. Bone-Targeted Therapies in Metastatic Castration-Resistant Prostate Cancer: Evolving Paradigms Wed, 28 Aug 2013 08:29:49 +0000 Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases. Joelle El-Amm, Ashley Freeman, Nihar Patel, and Jeanny B. Aragon-Ching Copyright © 2013 Joelle El-Amm et al. All rights reserved. A Pilot Study of Laparoscopic Doppler Ultrasound Probe to Map Arterial Vascular Flow within the Neurovascular Bundle during Robot-Assisted Radical Prostatectomy Wed, 19 Jun 2013 08:40:43 +0000 Purpose. To report on the feasibility of a new Laparoscopic Doppler ultrasound (LDU) technology to aid in identifying and preserving arterial blood flow within the neurovascular bundle (NVB) during robotic prostatectomy (RARP). Materials and Methods. Nine patients with normal preoperative potency and scheduled for a bilateral nerve-sparing procedure were prospectively enrolled. LDU was used to measure arterial flow at 6 anatomic locations alongside the prostate, and signal intensity was evaluated by 4 independent reviewers. Measurements were made before and after NVB dissection. Modifications in nerve-sparing procedure due to LDU use were recorded. Postoperative erectile function was assessed. Fleiss Kappa statistic was used to evaluate inter-rater agreement for each of the 12 measurements. Results. Analysis of Doppler signal intensity showed maintenance of flow in 80% of points assessed, a decrease in 16%, and an increase in 4%. Plane of NVB dissection was altered in 5 patients (56%) on the left and in 4 patients (44%) on the right. There was good inter-rater reliability for the 4 reviewers. Use of the probe did not significantly increase operative time or result in any complications. Seven (78%) patients had recovery of erections at time of the 8-month follow-up visit. Conclusions. LDU is a safe, easy to use, and effective method to identify local vasculature and anatomic landmarks during RARP, and can potentially be used to achieve greater nerve preservation. Ketan K. Badani, Edan Y. Shapiro, William T. Berg, Sarah Kaufman, Ari Bergman, Chris Wambi, Arindam RoyChoudhury, and Trushar Patel Copyright © 2013 Ketan K. Badani et al. All rights reserved. Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells Mon, 20 May 2013 15:27:57 +0000 Purpose. To determine whether Ski-interacting protein (SKIP) regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and uPA Inhibitor (PAI-1) in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA) compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment. Victor Villar, Jelena Kocic, and Juan F. Santibanez Copyright © 2013 Victor Villar et al. All rights reserved. HMGB1: A Promising Therapeutic Target for Prostate Cancer Sun, 12 May 2013 13:48:29 +0000 High mobility group box 1 (HMGB1) was originally discovered as a chromatin-binding protein several decades ago. It is now increasingly evident that HMGB1 plays a major role in several disease conditions such as atherosclerosis, diabetes, arthritis, sepsis, and cancer. It is intriguing how deregulation of HMGB1 can result in a myriad of disease conditions. Interestingly, HMGB1 is involved in cell proliferation, angiogenesis, and metastasis during cancer progression. Furthermore, HMGB1 has been demonstrated to exert intracellular and extracellular functions, activating key oncogenic signaling pathways. This paper focuses on the role of HMGB1 in prostate cancer development and highlights the potential of HMGB1 to serve as a key target for prostate cancer treatment. Munirathinam Gnanasekar, Ramaswamy Kalyanasundaram, Guoxing Zheng, Aoshuang Chen, Maarten C. Bosland, and André Kajdacsy-Balla Copyright © 2013 Munirathinam Gnanasekar et al. All rights reserved. Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer Wed, 08 May 2013 17:47:48 +0000 Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials. Jesal C. Patel, Benjamin L. Maughan, Archana M. Agarwal, Julia A. Batten, Tian Y. Zhang, and Neeraj Agarwal Copyright © 2013 Jesal C. Patel et al. All rights reserved. Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer Mon, 29 Apr 2013 15:14:21 +0000 Prostate cancer (PCa) is one of the most common malignancies found in males. The development of PCa involves several mutations in prostate epithelial cells, usually linked to developmental changes, such as enhanced resistance to apoptotic death, constitutive proliferation, and, in some cases, to differentiation into an androgen deprivation-resistant phenotype, leading to the appearance of castration-resistant PCa (CRPCa), which leads to a poor prognosis in patients. In this review, we summarize recent findings concerning the main deregulations into signaling pathways that will lead to the development of PCa and/or CRPCa. Key mutations in some pathway molecules are often linked to a higher prevalence of PCa, by directly affecting the respective cascade and, in some cases, by deregulating a cross-talk node or junction along the pathways. We also discuss the possible environmental and nonenvironmental inducers for these mutations, as well as the potential therapeutic strategies targeting these signaling pathways. A better understanding of how some risk factors induce deregulation of these signaling pathways, as well as how these deregulated pathways affect the development of PCa and CRPCa, will further help in the development of new treatments and prevention strategies for this disease. Henrique B. da Silva, Eduardo P. Amaral, Eduardo L. Nolasco, Nathalia C. de Victo, Rodrigo Atique, Carina C. Jank, Valesca Anschau, Luiz F. Zerbini, and Ricardo G. Correa Copyright © 2013 Henrique B. da Silva et al. All rights reserved. Blood Level Omega-3 Fatty Acids as Risk Determinant Molecular Biomarker for Prostate Cancer Mon, 25 Mar 2013 11:28:13 +0000 Previous researches involving dietary methods have shown conflicting findings. Authors sought to assess the association of prostate cancer risk with blood levels of omega-3 polyunsaturated fatty acids (n-3 PUFA) through a meta-analysis of human epidemiological studies in available online databases (July, 2012). After critical appraisal by two independent reviewers, Newcastle-Ottawa Quality Assessment Scale (NOQAS) was used to grade the studies. Six case control and six nested case control studies were included. Results showed nonsignificant association of overall effect estimates with total or advanced prostate cancer or high-grade tumor. High blood level of alpha-linolenic acid (ALA) had nonsignificant positive association with total prostate cancer risk. High blood level of docosapentaenoic acid (DPA) had significant negative association with total prostate cancer risk. Specific n-3 PUFA in fish oil, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) had positive association with high-grade prostate tumor risk only after adjustment of interstudy variability. There is evidence that high blood level of DPA that is linked with reduced total prostate cancer risk and elevated blood levels of fish oils, EPA, and DHA is associated with high-grade prostate tumor, but careful interpretation is needed due to intricate details involved in prostate carcinogenesis and N-3 PUFA metabolism. Mishell Kris Sorongon-Legaspi, Michael Chua, Maria Christina Sio, and Marcelino Morales Jr. Copyright © 2013 Mishell Kris Sorongon-Legaspi et al. All rights reserved. Circulating MicroRNAs as Biomarkers of Prostate Cancer: The State of Play Tue, 12 Mar 2013 15:50:26 +0000 MicroRNAs are key regulators of gene expression and play critical roles in both normal physiology and pathology. Recent research has demonstrated that these molecules are present in body fluids, such as serum, plasma, and urine, and can be readily measured using a variety of techniques. More importantly, emerging evidence suggests that circulating or urine miRNAs are useful indicators of disease. Here, we consider the potential utility of such miRNAs as noninvasive biomarkers of prostate cancer, a disease that would benefit substantially from novel diagnostic and prognostic tools. The studies aimed at identifying diagnostic, prognostic, and/or predictive miRNAs for prostate cancer are summarised and reviewed. Finally, practical considerations that will influence the translation of this recent research into clinical implementation are discussed. Nikhil Sapre and Luke A. Selth Copyright © 2013 Nikhil Sapre and Luke A. Selth. All rights reserved. Hypofractionated External-Beam Radiotherapy for Prostate Cancer Thu, 07 Mar 2013 16:46:52 +0000 There are radiobiological rationales supporting hypofractionated radiotherapy for prostate cancer. The recent advancements in treatment planning and delivery allow sophisticated radiation treatments to take advantage of the differences in radiobiology of prostate cancer and the surrounding normal tissues. The preliminary results from clinical studies indicate that abbreviated fractionation programs can result in successful treatment of localized prostate cancer without escalation of late toxicity. L. Chinsoo Cho, Robert Timmerman, and Brian Kavanagh Copyright © 2013 L. Chinsoo Cho et al. All rights reserved. Urologic Characteristics and Sexual Behaviors Associated with Prostate Cancer in an African-Caribbean Population in Barbados, West Indies Mon, 25 Feb 2013 13:21:31 +0000 Prostate cancer (PC) is the principal malignancy affecting African descent men in the Caribbean and the USA. Disparities in incidence, prevalence, and mortality in these populations are poorly understood. We evaluated the urologic characteristics and sexual behaviors of men with histologically confirmed PC (cases) and age-matched controls in the nationwide Prostate Cancer in a Black Population (PCBP) study conducted in Barbados. Cases were around 1.5 to 3 times more likely to report symptoms of prostatic enlargement, hematuria/hematospermia, and previous prostatitis. Sexually transmitted infections (STIs) were similar among cases (24.5%) and controls (26.7%). First sexual intercourse before the age of 16 was associated with an increased likelihood of both low- (Gleason score < 7; OR 1.63; 95% CI: 1.03–1.66) and high-grade PC (Gleason score ≥ 7; OR 1.82; 1.11–2.99). PC risk decreased with later age of sexual debut (). More lifetime sexual partners was associated with increased odds of high grade PC (). The contribution of sexual behaviors to the development and the outcomes of PC is likely due to multiple mechanisms, and further study will be necessary to elucidate the underlying pathophysiologic mechanisms in this and similar populations. Anselm J. M. Hennis, Suh-Yuh Wu, Barbara Nemesure, and M. Cristina Leske Copyright © 2013 Anselm J. M. Hennis et al. All rights reserved. Analysis of Preoperative Detection for Apex Prostate Cancer by Transrectal Biopsy Thu, 21 Feb 2013 09:05:03 +0000 Background. The aim of this study was to determine concordance rates for prostatectomy specimens and transrectal needle biopsy samples in various areas of the prostate in order to assess diagnostic accuracy of the transrectal biopsy approach, especially for presurgical detection of cancer in the prostatic apex. Materials and Methods. From 2006 to 2011, 158 patients whose radical prostatectomy specimens had been evaluated were retrospectively enrolled in this study. Concordance rates for histopathology results of prostatectomy specimens and needle biopsy samples were evaluated in 8 prostatic sections (apex, middle, base, and transitional zones bilaterally) from 73 patients diagnosed at this institution, besides factors for detecting apex cancer in total 118 true positive and false negative apex cancers. Results. Prostate cancer was found most frequently (85%) in the apex of all patients. Of 584 histopathology sections, 153 (49%) from all areas were false negatives, as were 45% of apex biopsy samples. No readily available preoperative factors for detecting apex cancer were identified. Conclusions. In Japanese patients, the most frequent location of prostate cancer is in the apex. There is a high false negative rate for transrectal biopsy samples. To improve the detection rate, transperitoneal biopsy or more accurate imaging technology is needed. Tomokazu Sazuka, Takashi Imamoto, Takeshi Namekawa, Takanobu Utsumi, Mitsuru Yanagisawa, Koji Kawamura, Naoto Kamiya, Hiroyoshi Suzuki, Takeshi Ueda, Satoshi Ota, Yukio Nakatani, and Tomohiko Ichikawa Copyright © 2013 Tomokazu Sazuka et al. All rights reserved. Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent Wed, 13 Feb 2013 08:36:16 +0000 Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world. Timothy R. Rebbeck, Susan S. Devesa, Bao-Li Chang, Clareann H. Bunker, Iona Cheng, Kathleen Cooney, Rosalind Eeles, Pedro Fernandez, Veda N. Giri, Serigne M. Gueye, Christopher A. Haiman, Brian E. Henderson, Chris F. Heyns, Jennifer J. Hu, Sue Ann Ingles, William Isaacs, Mohamed Jalloh, Esther M. John, Adam S. Kibel, LaCreis R. Kidd, Penelope Layne, Robin J. Leach, Christine Neslund-Dudas, Michael N. Okobia, Elaine A. Ostrander, Jong Y. Park, Alan L. Patrick, Catherine M. Phelan, Camille Ragin, Robin A. Roberts, Benjamin A. Rybicki, Janet L. Stanford, Sara Strom, Ian M. Thompson, John Witte, Jianfeng Xu, Edward Yeboah, Ann W. Hsing, and Charnita M. Zeigler-Johnson Copyright © 2013 Timothy R. Rebbeck et al. All rights reserved. Androgen Receptor-Target Genes in African American Prostate Cancer Disparities Thu, 10 Jan 2013 16:27:46 +0000 The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging (“transcriptional convergence”) on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs. Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas Jarrett, Harold Frazier, Steven R. Patierno, and Norman H. Lee Copyright © 2013 Bi-Dar Wang et al. All rights reserved. The Role of Targeted Focal Therapy in the Management of Low-Risk Prostate Cancer: Update on Current Challenges Mon, 31 Dec 2012 15:20:33 +0000 Prostate cancer is one of the most prevalent cancers among men in the United States, second only to nonmelanomatous skin cancer. Since prostate-specific antigen (PSA) testing came into widespread use in the late 1980s, there has been a sharp increase in annual prostate cancer incidence. Cancer-specific mortality, though, is relatively low. The majority of these cancers will not progress to mortal disease, yet most men who are diagnosed opt for treatment as opposed to observation or active surveillance (AS). These men are thus burdened with the morbidities associated with aggressive treatments, commonly incontinence and erectile dysfunction, without receiving a mortality benefit. It is therefore necessary to both continue investigating outcomes associated with AS and to develop less invasive techniques for those who desire treatment but without the significant potential for quality-of-life side effects seen with aggressive modalities. The goals of this paper are to discuss the problems of overdiagnosis and overtreatment since the advent of PSA screening as well as the potential for targeted focal therapy (TFT) to bridge the gap between AS and definitive therapies. Furthermore, patient selection criteria for TFT, costs, side effects, and brachytherapy template-guided three-dimensional mapping biopsies (3DMB) for tumor localization will also be explored. Daniel W. Smith, Diliana Stoimenova, Khadijah Eid, and Al Barqawi Copyright © 2012 Daniel W. Smith et al. All rights reserved. Androgen Deprivation Therapy Toxicity and Management for Men Receiving Radiation Therapy Sun, 30 Dec 2012 18:01:18 +0000 Androgen deprivation therapy is commonly used in combination with radiotherapy as part of the definitive treatment for men with clinically localized and locally advanced prostate cancer. Androgen deprivation has been associated with a wide range of iatrogenic effects impacting a variety of body systems including metabolic, musculoskeletal, cardiovascular, neurocognitive, and sexual. This review aims to provide the radiation oncology community with the knowledge to monitor and manage androgen deprivation therapy toxicity in an effort to provide the highest level of care for patients and to minimize the iatrogenic effects of androgen deprivation as much as possible. Matthew E. Johnson and Mark K. Buyyounouski Copyright © 2012 Matthew E. Johnson and Mark K. Buyyounouski. All rights reserved.