bluuebunny/crossref_metadata_2025 huggingface dataset:
Population based PSA screening in Mexico City.
Authors: Herrera-Caceres Jaime Omar , Gonzalez-Cuenca Eduardo , Manzanera Andrea G. , Aguilar Laura K. , Aguilar-Cordova Estuardo , Castillejos-Molina Ricardo Alonso , Feria Bernal Guillermo
Published: March 2017

92

Background: Since the U.S. Preventive Task Force recommended against PSA screening in 2012, the polemic between the benefit of early detection and the risk of early overtreatment, has been heightened. Furthermore, in countries where diagnosis is delayed even in symptomatic men and resources are limited for treating advanced disease, the impact of limiting PSA screening may be greater resulting in a shorter incidence/mortality ratio. In Mexico PSA screening is not widely used and many men are never diagnosed with PCa. Thus, the true incidence of PCa is unknown and yet it is the number one cause of cancer morbidity and mortality in men. The current study was designed to evaluate the incidence of PCa in a random population of men from Mexico City using PSA screening. Methods: Prospective enrollment of 3,837 men > 50 years old without previous history of PCa underwent PSA testing. Men with a PSA > 4ng/ml were selected for a second analysis and for completion of a questionnaire on prostate health history. Men with confirmed elevated PSA are being invited to further evaluation and possible biopsy by a urologist. Results: Median age was 59 years (interquartile range 56 to 63 years). In this cohort, 412 (10.8%) men had a total PSA > 4ng/ml (5% of those < 55 years vs. 26% of those > 70 years). From these men, 284 had a repeat PSA approximately 3 months after the first evaluation (median 98 days). A total of 229 men had a 2nd PSA above 4mg/ml, 25 had PSA > 20ng/ml. During evaluations, 309 men completed the questionnaire showing that 29% had previous PSA testing, 11% had a previous DRE, 4% had history of a previous biopsy and 2% identified having a family history of PCa. Conclusions: Greater than 10% (n = 412/3837) of men from a random screen in Mexico City were found to have elevated PSA ( > 4ng/ml). Of these, 12% (n = 48) and 6% (n = 25) had levels consistent with intermediate- and high-risk disease, respectively. Most of these ”high-PSA” patients did not have a previous PSA evaluation despite symptoms, representing a considerable number of patients in whom screening could be life-saving intervention. A low awareness of family history of PCa could be representative of both the lack of diagnosis of PCa and general ignorance regarding this disease. We continue evaluating and doing biopsies to patients with indication.
Pre-treatment PSA- progression as a negative prognostic factor in patients using 5-alpha-reductase inhibitors prior to radiotherapy for prostate cancer.
Authors: Taussky Daniel , Piotte Julie , Zorn Kevin , Zanaty Marc , Krishnan Vimal , Bahary Jean-Paul , Beauchemin Marie-Claude , Barkati Maroie , Menard Cynthia , Delouya Guila , Lambert Carole
Published: March 2017

96

Background: To investigate the impact of 5-alpha-reductase inhibitors (5-ARIs) usage on radiotherapy outcomes for localized prostate cancer. Methods: From our institutional database of over 2500 patients, we identified 203 patients on a 5-ARI. They were all treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients receiving a 5-ARI were analyzed according to the following prostate cancer progression criteria: a) progression of Gleason score or increase in cancer volume on the biopsy, b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis. Results: At a median follow-up of 36 months (interquartile range [IQR] 22-52 months), 10 (4.9%) patients experienced BF. 52% of men demonstrated none of the progression criteria, 37% showed only one prostate cancer progression criteria and 11% showed two. Using a univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) but not Gleason progression (p = 0.3) were a significant predictive factor of BF. With separate multivariate analysis adjusted for the CAPRA score (HR 1.7, 95% CI 1.2-2.3, p = 0.003), a rising PSA (HR 5.7, 95% CI 1.1-28.8, p = 0.04) and the number of cancer progression factors (HR 2.9, 95%CI 1.2-7.0, p = 0.02) remained adverse risk factors. Both Gleason score progression (p = 0.4) and first biopsy positive for cancer (p = 0.13) failed to remain significant. Age and obesity were not significant factors in univariate or multivariate analysis. Conclusions: A PSA progression experienced while under 5-ARI treatment before EBRT or brachytherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy.
CANCAP02: A study into the pharmacodynamic biomarker effects of vistusertib (AZD2014), an mTORC1/2 inhibitor, given prior to radical prostatectomy (RP).
Authors: Pacey Simon , Garcia Corbacho Javier , Shah Nimish , Bratt Ola , Warren Anne , Baird Richard D. , Gnanapragasam Vincent , Stearn Sara , Ingle Susan , Bell Leanne K , Dott William , Qian Wendi , Zhao Wanfeng , Davies Barry , Harrington Elizabeth A. , Oelmann Elisabeth Maria , Hategan Mirela , Kumar Sanjeev
Published: March 2017

97

Background: Additional systemic therapy given to unselected patients (pts) around RP has yet to improved pt survival. Further trials should use appropriate pt selection, i.e. men at highest risk of relapse, ideally biomarker stratified. Using novel drugs prior to RP allows direct study of effects in primary prostate cancer (PC) that may guide design of future trials. Altered PI3K/AKT/mTOR pathway signalling is associated with aggressive PC hence we have undertaken a study vistusertib, an oral, dual mTORC1/mTORC2 inhibitor prior to RP. Methods: Primary endpoint was to measure mTOR1/2 inhibition by immunohistochemistry (IHC). Secondary endpoints were feasibility, safety, tolerability and determining plasma concentrations of vistusertib. Exploratory objectives included measurement of anti-cancer effects. Men, due for RP, with high volume or aggressive PC consented and received vistusertib, 50mg bd, for 15 days prior to RP. Diagnostic biopsy and RP tissue were collected for IHC. Adverse events (AE) were graded according to CTCAE v4. Plasma was collected to determine vistusertib concentrations. Results: 21 men, median age 62 (range 50 – 69) included 11 intermediate and 10 high risk PC. 18/21 were evaluable for primary endpoint. On day of RP mean plasma vistusertib concentration at RP was 648 ng/mL (range 386-852) and 6-8 hr post dose 484 ng/mL (range 211-660). Majority of related AEs were Grade (Gr) 1, the most common being rash, thrombocytopenia, oral mucositis, diarrhoea, lymphopenia and fatigue. Six pts experienced Gr3 AEs (3 pt lymphopenia, 1 pt each rash, mucositis and ALT rise). Two pts discontinued due to AEs (mucositis, thrombocytopenia) and one withdrew consent. Surgery was delayed in one pt (Gr 1 thrombocytopenia). IHC confirmed at RP: 4EBP1 was reduced in 100% pt (75% no staining post vistusertib) and pS6 was reduced in 67%, not changed in 25% and increased in 8%. A fall in PSA occurred in 4/18 pts. Conclusions: 2 weeks of AZD2014 can be given prior to RP. Active plasma concentrations were achieved. mTOR pathway inhibition was confirmed on IHC and a PSA fall occurred in 22% of pt. Analysis is ongoing, to be informed by concomitant studies in a PTEN null PC model. Clinical trial information: NCT02064608.
Focal therapy for prostate cancer: Attitude and practice patterns.
Authors: Jain Amit L , Sidana Abhinav , Maruf Mahir , Sugano Dordaneh , Calio Brian P. , Wood Bradford J. , Pinto Peter A.
Published: March 2017

e541

Background: Focal therapy (FT) for localized prostate cancer (PCa) has been shown to have encouraging short term oncological outcomes, excellent preservation of functional outcomes and is increasing in popularity in Urologic community. We aim to evaluate the preferences and practice trends among urologists regarding this upcoming treatment strategy. Methods: An anonymous online questionnaire was designed to collect information on urologists’ views and use of focal therapy. The survey was sent to members of the Endourological Society (ES) and American Urological Association (AUA). Multivariate logistic regression analysis was done to determine predictors for utilization of FT for localized prostate cancer. Results: A total of 383 responses were received [AUA: 342, ES: 41]. Mean age of respondents was 43(±11.2) years. Although about half of the respondents (51.4%) believed FT to be moderate to extremely beneficial in the treatment of PCa, only 23% (89) of the respondents currently utilize FT in their practice. While the most common setting for utilization of FT was in patients with unilateral intermediate risk (75.2%) PCa, a small percentage of respondents also used FT for patients with bilateral intermediate risk and unilateral high risk PCa (9% and 7% respectively). The most common FT modality was Cryoablation in 62% followed by High Intensity Focused Ultrasound in 44%. Most common reasons for not using focal therapy were the lack of belief in ‘index lesion theory’ (186) (63.2%) followed by the lack of experience (121) (41.1%). About 58.2% respondents would use FT often in an office or outpatient setting if they had access to reliable and cost effective options. Surgeon’s experience (practice for more than 15 years) (p = 0.035) was the only independent predictor for utilizing FT in localized PCa. Conclusions: Only a quarter of our respondents utilize FT in their practice with surgeon’s experience being the only independent predictor for utilizing FT. Majority of respondents though consider FT to be beneficial in prostate cancer management would use it more often if they provided more reliable and cost effective options. Over time experience and accessibility to reliable methods to perform FT may lead to further use of this novel treatment.
Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: A single-center study.
Authors: Hagiwara Kazuhisa , Koie Takuya , Tobisawa Yuki , Yamamoto Hayato , Imai Atsushi , Yoneyama Tohru , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: March 2017

e542

Background: The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) for high-risk Pca patients treated with neoadjuvant therapy comprising a luteinizing hormone-releasing hormone agonist plus low-dose estramustine (LHRH agonist + EMP) prior to radical prostatectomy (RP). In the present study, we evaluated the efficacy of neoadjuvant therapy comprising a gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate (GnRH antagonist + EMP) in patients with high-risk Pca. Methods: Between September 2005 and March 2016, we identified 406 high-risk Pca patients of whom 136 received neoadjuvant GnRH antagonist + EMP and 270 received LHRH agonist + EMP before RP. We retrospectively evaluated the clinical and pathological covariates between the two groups. The primary endpoint was the rate of pathological ≤ T2 status, and the secondary endpoint was BRFS. Results: The rates of pathological ≤ T2 status were 80.2% and 61.5% in the GnRH antagonist + EMP and LHRH agonist + EMP groups, respectively ( P < 0.001). The 3-year BRFS rates were 97.8% and 85.2% in the GnRH antagonist + EMP and LHRH agonist + EMP groups, respectively ( P = 0.021). Multivariate analysis revealed that biopsy Gleason score, GnRH antagonist + EMP, and clinical T stage were independent predictors of pathological ≤ T2 status in surgical specimens. Conclusions: Our findings suggest that neoadjuvant GnRH antagonist + EMP followed by RP may improve the pathological outcomes and reduce the risk of biochemical recurrence in patients with high-risk Pca. Further prospective studies to confirm these findings are warranted.
The impact of extended lymph node dissection versus neoadjuvant therapy with limited lymph node dissection on biochemical recurrence in high-risk prostate cancer patients treated with radical prostatectomy: A multi-institutional analysis.
Authors: Koie Takuya , Ookubo Teppei , Mitsuzuka Koji , Narita Shintaro , Inoue Takamitsu , Kawamura Sadafumi , Tochigi Tatsuo , Habuchi Tomonori , Arai Yoichi , Ohyama Chikara , Yoneyama Takahiro
Published: March 2017

e543

Background: The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) in high-risk Pca patients treated with neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low-dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). The aim of this study was to assess whether neoadjuvant LHRH+EMP confers an oncological benefit for high-risk Pca compared to extended lymph node dissection (e-PLND). Methods: The Michinoku Urological Cancer Study Group database contained the data of 2403 consecutive Pca patients treated with RP at 4 institutes between March 2000 and December 2014. In the e-PLND group, we identified 238 high-risk Pca patients who underwent RP and e-PLND, with lymphatic tissue removal around the obturator and the external iliac regions, and hypogastric lymph node dissection. The neoadjuvant therapy with limited PLND (l-PLND) group included 280 high-risk Pca patients who underwent RP and removal of the obturator node chain between September 2005 and June 2014 at Hirosaki University. The neoadjuvant LHRH+EMP therapy included the administration of 280 mg/day of LHRH and EMP for 6 months before RP. The outcome measure was BRFS. Results: The 5-year BRFS rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9% and 54.7%, respectively ( P < 0.0001). The operative time was significantly longer in the e-PLND group compared to that of the neoadjuvant therapy with l-PLND group. Grade 3/4 surgery-related complications were not identified in both groups. Conclusions: Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP might reduce the risk of biochemical recurrence.
Can frequency of prostate biopsy on active surveillance be reduced without significantly increasing risk?
Authors: Auffenberg Gregory , Barnett Christine , Cheng Zian , Yang Fan , Wang Jiachen , Miller David Christopher , Montie James E. , Mamawala Mufaddal , Denton Brian
Published: March 2017

e546

Background: The goal of this investigation is to use longitudinal Active Surveillance (AS) data to identify whether biopsies could be eliminated from a 10-year AS plan calling for annual biopsy without substantially prolonging the time to detection of prostate cancer (CaP) grade progression. Methods: With data from 1,500 men with very-low or low-risk CaP enrolled in AS at Johns Hopkins, we developed a hidden Markov model to estimate probabilities of progression to Gleason 7 or higher. We then simulated all potential AS biopsy strategies where it was assumed biopsy would be performed no more often than annually and either would or would not be performed each year after diagnosis. For every strategy the model was used to predict the average time from occurrence to the detection of grade progression. Potential alternatives to annual biopsy were identified. Results: The estimated 10 year probability of grade progression was 40.0% and the annual probability was 4.0%. Simulation of an annual biopsy strategy estimated that for men who experience grade progression the mean time from occurrence to detection would be 14.1 months. Alternative strategies that reduced the number of biopsies received over 10 years increased the time to detecting grade progression; however several strategies eliminated biopsies with only small increases in the time to detecting grade progression (Table). For instance, a strategy calling for 6 biopsies over 10 years (biopsies in years 1-3,5,7, and 8) would only increase the average time to detecting grade progression by 4.6 months while eliminating 4 biopsies. Conclusions: While annual biopsy was associated with the shortest interval to detecting grade progression, several alternative strategies may allow for less frequent biopsy without sizable increases in time to detecting grade progression. [Table: see text]
Comparison of conventionally fractionated and hypofractionated schedule for post-prostatectomy salvage radiotherapy: Early results from non-randomized observational study.
Authors: Murgic Jure , Jaksic Blanka , Kruljac Ivan , Prpic Marin , Budanec Mirjana , Mrcela Iva , Gregov Marin , Prgomet Angela , Kust Davor , Mlinaric Mihaela , Spajic Borislav , Frobe Ana
Published: March 2017

e551

Background: Data on hypofractionated radiotherapy in definitive treatment of prostate cancer are maturing; however, limited information is available for hypofractionated radiotherapy after prostatectomy. We aimed to compare hypofractionated and conventionally fractionated radiotherapy in salvage setting for biochemically recurrent prostate cancer. Methods: A retrospective analysis was performed in 106 patients with proven PSA recurrence treated to the prostate bed. Patients were non-randomly, in a alternating fashion, subjected to either 52.5 Gy in 20 fractions of 2.625 Gy over 4 weeks (N = 57, hypofractionated group) or 66 Gy in 33 fractions of 2 Gy over 6.5 weeks (N = 49, conventionally fractionated group). There was no statistically significant difference in pathologic T-stage and Gleason score distribution between the groups. In the conventionally fractionated group there were more patients with positive margins (p = 0.01), more prevalent concomitant hormonal therapy (50.9% vs 61.2%, p = 0.001), but less long-term hormonal therapy (21.4% vs 81%, p < 0.001), compared to hypofractionated group. Median follow-up was 20 months (range 6-36 months). Failure (PSA nadir+0.2) rates between the groups were compared using Cox proportional hazards model. Radiation-related side-effects were assessed using RTOG scoring scale. Results: At this early point, 13 patients (22.8%), and 6 patients (12.2%) experienced treatment failure in the hypofractionated group and conventionally fractionated group, respectively (HR 3.1, 95%CI (1.5-6.3)). More late grade 2 gastrointestinal and genitourinary side-effects were observed in conventionally fractionated group (4.1% vs 1.8%, and 2% vs 0%, p = 0.01, respectively). No grade 3 toxicities were observed. Conclusions: More initial biochemical failures were observed in hypofractionated group compared to conventionally fractionated group. However, baseline heterogeneity between the groups and short follow-up preclude any causal observation of differential efficacy between these two schedules. Randomized phase II trial is planned to prospectively compare these two regimens.
Aspirin use in robot-assisted radical prostatectomy? Systematic review and metanalysis.
Authors: Carneiro Arie , Cha Jonathan Doyun , Wroclawski Marcelo Langer , Kayano Paulo Priante , Claros Oliver Rojas , Moran Natasha Kouvaleski Saviano , Serpa Ary , Lemos Gustavo Caserta
Published: March 2017

e553

Background: Low dose aspirin (81-100mg) used as secondary prevention in cardiovascular diseases is correlated with increased bleeding and overall complications in surgical procedures. However, the suspension of this medication can increase the risk of cerebrovascular accident and myocardial infarction. Robot-assisted radical prostatectomy (RARP) has significantly decreased the surgical morbidity and the peri-operative bleeding. Our aim was to analyze whether RARP is feasible and safe in patients with low dose aspirin intake. Methods: Systematic review of the literature using MEDLINE, ESCOPUS, Lilacs, Scielo and Cohcrane articles published until June 2016. We included prospective trials and large cohorts that evaluated patients with (Group A) or without the maintenance of aspirin (Group B). Results: 5 trials (n = 1481 men) were included. One thousand and thirteen men stopped the use of the medication and 168 kept it during the peri-operatory setting, including the procedure. For the analyses of overall complications 3 articles with 458 men were included. The overall complication rate was 19%, without statistically significant difference between groups (Group A: 10.5%; Group B: 21.8% - OR: 0.70 IC:0.31- 1.56; I2= 0%). In a sub analysis evaluating major complications (Clavien > 2), cardiovascular events were similar between groups (Group A: 10.5%; Group B: 19% OR: 0.67 IC: 0.34- 1.70; I2= 0%). There were 5 trials included to evaluate blood loss, with 1481 patients (168 Group A and 1313 Group B). The overall transfusion rate was 1.9%, without difference between groups (Group A = 3,5% and Group B = 1.7% - OR:3.24 IC:0.87- 12.06; I2= 0%). The estimate perioperative bleeding rate was significantly lower in patients using aspirin during surgery (OR:-33.74 IC:-44.99, -22.49, I2= 92%). The hospital stay length was similar between groups (OR:0 IC:-0.04, 0.04; I2= 0%). Conclusions: Low dose aspirin does not correlate with larger peri-operatory surgical morbidity, transfusion rate or hospital stay. The blood loss was lower in the aspirin intake group, but this fact should be interpreted with caution due to the high heterogeneity among studies. RARP in patients under continuous aspirin intake was feasible and safe.
Does the EPIC-26 measure five domains in English and Spanish speakers?
Authors: Mir Maria Carmen , Perera Marisa , Garin Olatz , Ferrer Montserrat , Fumadó Lluis , Punnen Sanoj , Balise Raymond R , Westrick Ashly
Published: March 2017

e557

Background: Despite being widely used in many countries to assess health-related quality of life for patients undergoing treatment for localized prostate cancer(PC), seldom research has been done to investigate the five domain scores generated by 26 question short form of the Expanded Prostate Cancer Index Composite Short (EPIC-26). We conducted exploratory and confirmatory factor analyses searching for evidence of five unique domains of dysfunction in men being treated for PC in the US and Spain.Methods: Using two-year post treatment information, data from 400 men who were part of the original EPIC (OE) validation cohort [T1 or T2, 87% Radical Prostatectomy (RP), 10% External Beam Radiation (EBR), 3% Brachytherapy (BR)] and 450 men who were treated for prostate cancer at Institut Hospital del Mar d'Investigacions Mèdiques in Spain [33% RP, 33% EBR, 33% BR], were subjected to exploratory (EFA) and confirmatory factor analysis (CFA).Results: EFA analyses on both the OE and Spanish cohorts provides support for three, four or five factor models (accounting for approximately 83, 91 or 97% of variance in either cohort) to describe the EPIC-26 variables and weak evidence for the hormonal domain. There is evidence of separate urinary, sexual and bowel factors, but limited evidence of a separate hormonal domain. With the exception of the questions which could be described as assessing depression (lack of energy and depression and in some models weight gain), items within the hormonal domain frequently failed to consistently load onto a single factor (orthogonal communalities ranging from .22 to .27 in the OE cohort and .10 to .21 in the Spanish for hot flashes, breast tenderness and weight gain). CFA looking for the published five domain solution in the Spanish data provides mediocre support for a five factor solution (Standardized RMR = .0624, RMSEA Estimate = .07, Bentler Comparative Fit Index = .91). Conclusions: While all questions asked on the EPIC-26 are of clinical value, there is limited evidence to continue to treat the hormonal domain as a single entity. Urologists should consider looking at the questions linked to depression separately from the other hormonal questions
Angiomotin to regulate prostate cancer cell proliferation by signaling through Hippo-YAP pathway.
Authors: Shen Pengfei , Zeng Hao , Ortiz Angelica , Cheng Chien-Jui , Lee Yu-Chen , Yu Guoyu , Lin Song-Chang , Yu-Lee Li-Yuan , Lin Sue-Hwa
Published: March 2017

e559

Background: Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. Methods: Purified GST-AMOTp80 was used as immunogen for antibody generation. Real-time PCR, western blot and immunohistochemistry were used to identify the expression of AMOT. To study the function of AMOT, retroviral vector were constructed, also shRNA was used to knockdown AMOT in cells. Cell migration and invasion assays were performed by using transwell chambers. Nuclear and cytoplasmic protein fractions were prepared by using NE-PER reagents (Pierce). The SPSS 19.0 software was used for statistical analysis. Chi-square test and t test were used for the comparisons between groups. Results: AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80 functioned as a tumor promoter by enhancing PCa cell proliferation while AMOTp130 did not. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting the nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Conclusions: Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.
Effect of incorporation of preoperative CT scan on bladder doses and irradiated volume in postprostatectomy radiation therapy (pPRT).
Authors: Akhtari Mani , Yuan Denley Ming Kee , Endres Eugene C. , Tran Bao Minh , Swanson Todd A.
Published: March 2017

e561

Background: pPRT increases local control, biochemical progression free survival, and even overall survival in patients with adverse features undergoing prostatectomy. The Radiation Therapy Oncology Group (RTOG) consensus definition of the clinical target volume (CTV) in 2010 was based on patterns of failure and anatomy without consideration of pre-operative imaging. This results in large volumes of bladder in the treatment field. Our study evaluates whether incorporation of pre-operative prostate volume can reduce the post-operative CTV and minimize dose to adjacent normal tissue. Methods: We reviewed records of all patients with available pre-operative pelvic CT scans treated at our institution with pPRT. The pre-operative CT scan was fused to the simulation CT. Post-operative CTV (CTV1) was delineated based on RTOG guidelines. A separate CTV (CTV2) was constructed, based on the intact prostate and proximal seminal vesicles. Plans were constructed for each CTV and doses to rectum, bladder, and penile bulb calculated, as well as concordance between the two CTVs and planning target volumes (PTVs). Paired student’s t-test was used to calculate difference between doses in the two different plans. Results: 10 patients’ plans were analyzed. Dosimetric parameters are shown in table 1. Volume of the bladder receiving 65 Gy or higher (V65) was significantly higher in CTV1. As would be expected, there were no significant differences in dose to either the rectum or penile bulb. Additionally, there was on average only 39% overlap between the CTVs and 60% between the PTVs in the two plans. Conclusions: Utilization of the pre-operative pelvic CT scan can aid in more accurate delineation of the CTV/PTV in prostate bed radiation therapy and decrease the bladder dose. As many patients at risk for pPRT have had this imaging performed preoperatively, in accordance with guidelines, incorporation of this data appears prudent. These findings need to be validated in a larger cohort. [Table: see text]
Impact of castration resistant status on overall survival for prostate cancer patients treated with radical prostatectomy.
Authors: Fujita Naoki , Koie Takuya , Yamamoto Hayato , Imai Atsushi , Tobisawa Yuki , Yoneyama Tohru , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: March 2017

e562

Background: We estimated the natural history and predictive factors of oncological outcomes in patients with prostate cancer (PCa) after radical prostatectomy (RP). Methods: In this retrospective study, we reviewed the clinical and pathological records of 1083 PCa patients who underwent RP and bilateral pelvic lymphadenectomy with or without neoadjuvant therapy between July 1996 and December 2014 at Hirosaki University. All patients were followed-up by assessing serum prostate-specific antigen (PSA) and testosterone levels every 3 months for 5 years and every 6 months thereafter. The endpoint was the oncological outcomes after surgery. Univariate analyses were performed using the Kaplan-Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model. Results: The 5-year and 10-year overall survival rates were 98.5 % and 92.0 %, respectively. At the end of the study, 226 patients (20.8%) showed biochemical recurrence and 28 patients (2.6%) had developed castration-resistant Pca (CRPC). The patients with CRPC were significantly poor prognosis compared with those without CRPC (P < 0.01). On multivariate analysis, although preoperative variables were no significant differences, only CRPC was significantly associated with OS. Conclusions: RP was shown to provide excellent long-term survival with OS at 10 years. In addition, a small proportion of the patients treated with RP had CRPC and died of Pca within 10 years. Development to castration resistant status may have critical impact on OS.
MILGa-01: A first-in-human study assessing the safety and tolerability of chMIL-38 in metastatic prostate, bladder, and pancreatic cancers.
Authors: Gurney Howard , Sabanathan Dhanusha , Gillatt David , Poursoultan Pirooz , Ho Shon Kevin , Walsh Brad , Velonas Vicki , Thurecht Kristofer , Campbell Douglas
Published: March 2017

e565

Background: Metastatic or recurrent cancer continues to be a challenge in patients with urogenital and pancreatic cancers despite the development of newer anti-androgen therapies. MIL-38 is an IgG1 murine monoclonal antibody directed against Glypican-1 (GPC-1). The proteoglycan GPC-1 is upregulated in prostate, pancreatic and bladder cancer cell lines. Targeting of tumor xenografts and lack of adverse events in pre-clinical models suggest chimeric MIL-38 (chMIL-38) is a good candidate for both radioimmunotherapy and antibody-drug conjugate development. Methods: Patients with known metastatic prostate and pancreatic cancer were injected with a single dose of MILGa drug (1mg, 250MBq dose) and imaged with whole body gamma camera scans and SPECT/CT at 30 minutes, 6 h, 24 h, 48 h, 72 h (if required) and 144h post infusion. Blood and urine samples for pharmacokinetic, biomarker studies, cancer markers and hematology and biochemistry analysis were collected at each time point. Dosimetry analysis of tumour images was performed to determine the relative accumulation of MILGa in different organs. Results: To date one pancreatic cancer patient and one prostate cancer patient with metastatic disease have been infused with the MILGa drug. The drug was safe and well tolerated in both patients with no infusion reactions or drug-related adverse events. Tracer uptake was observed in the liver, with mild tracer uptake in the spleen, skeletal system and kidneys. Significant MILGa targeting was seen in Patient 2 24 hours post infusion onwards with uptake in the right foot (right calcaneum and cuneiform bones). SPECT/CT at 24 hours confirmed uptake was in the bone, not in the joint space or soft tissue. Conclusions: MILGa has shown a promising safety profile to date with indication of tumour targeting in metastatic prostate cancer. Additional data from this study may permit the selection and evaluation of potentially sensitive tumor types to be studied for further therapeutic and diagnostic studies. Clinical trial information: ACTRN12616000787482.
Refill gaps and dose reductions in patients treated with abiraterone acetate plus prednisone (AA+P) or enzalutamide (ENZ).
Authors: Pilon Dominic , Behl Ajay S. , Emond Bruno , Xiao Yongling , Lefebvre Patrick , Kane Christopher J.
Published: March 2017

e572

Background: Recently available treatmentssuch as AA+P or ENZ have improved survival and quality of life for patients with metastatic castrate resistant prostate cancer (mCRPC). However, drug-drug interactions, intolerance or toxicities can potentially lead to dose reductions or treatment interruption. This study assessed refill gaps and dose reduction events in patients treated with AA+P or ENZ. Methods: The MarketScan databases (03/2012-10/2015) were used to conduct a retrospective analysis. Patients initiated on AA+P or ENZ (index date) after 09/2012 with ≥ 6 months of continuous eligibility prior to index date and ≥ 1 diagnosis for prostate cancer were included. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Weighted Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare the occurrence of refill gaps ( ≥ 14, ≥ 30, or ≥ 60 days) or dose reductions (i.e., relative dose intensity [RDI] ≤ 80%, and ≤ 85%) between groups. RDI was calculated as the ratio of the delivered dose intensity (total delivered dose divided by the period over which the total dose was measured) to the standard dose intensity as recommended in the package insert for AA+P or ENZ. Results: A total of 2,540 AA+P and 1,265 ENZ patients were identified. IPTW resulted in balanced baseline demographic, comorbidities, and disease characteristics. At 12 months post-index, patients initiated on ENZ were more likely to have an RDI ≤ 80% or ≤ 85% or to have a refill gap ≥ 30 or ≥ 60 days when compared to patients initiated on AA+P (Table). Conclusions: This study showed that mCRPC patients treated with ENZ were more likely to experience a refill gap and to reduce their treatment dose than patients treated with AA+P. [Table: see text]
A probabilistic threshold analysis of metformin (Met) with enzalutamide (Enza) to determine the cost and added efficacy needed to make such a combination theray cost-effective (CE).
Authors: Hill Jordan , Venner Peter , Paulden Mike , McCabe Christopher , North Scott A. , Danielson Brita Lavender , Usmani Nawaid
Published: March 2017

e577

Background: Enza has become known for its' effectiveness in treating patients with metastatic castrate-resistant prostate cancer. However, Enza is expensive (~$3175/month) and unlikely to be CE at any willingness to pay (WTP) threshold from $0-$125 000/quality-adjusted life years (QALYs). Met is inexpensive (~$8.00/month) and recently two large population-based studies of prostate cancer (PCa) demonstrated that diabetics taking Met had improved PCa specific and overall survival compared to those not taking Met. As a result we theorized that there must be a cost of Enza and a specific added effect Met could provide that would make Met a CE adjuvant therapy to Enza even though it is not currently used as such. Methods: We constructed a Markov-based decision analytic model and performed a probabilistic threshold analysis to narrow in on several combinations of costs of Enza and added efficacies needed to make Enza + Met a CE combination therapy at different WTP thresholds. Costs, utilities, and transition probabilities were derived from existing literature. Effectiveness was measured using QALYs. Costs and QALYs were considered over a lifetime horizon and discounted at 5% per annum. Results: At a WTP threshold of $50 000/QALY Enza + Met is unlikely to be CE no matter the cost decrement or added efficacy applied to the model. At a WTP threshold of $75 000/QALY Met is also unlikely to be CE unless the price of Enza could drop to $1934/month and Met could also add 1% to the efficacy of Enza. At Enza's current cost and a WTP threshold of $100 000, Enza + Met could be CE barring Met adds 0.621% to the number of patients still on treatment at 36 months. Conclusions: Enza + Met is unlikely to be CE at WTP thresholds of $50 000/QALY or $75 000/QALY unless there is a significant price drop for Enza; these results make sense because a therapy that is considered not CE at these WTP thresholds by itself is unlikely to be CE with a theoretical adjuvant therapy that would hold a patient on such a treatment for even longer. Our results show that the only way for Enza + Met to be CE is through the theoretical overall survival benefit of Met as the price of Enza is unlikely to drop any time soon.
3D-microdevice for the in vivo capture of cancer-associated circulating cells.
Authors: Cayron Hélène , Jiménez Zenteno Alejandro Kayum , Esteve Aurore , Sanson Sylvain , Vieu Christophe , Malavaud Bernard Andre , Cerf Aline
Published: March 2017

e579

Background: Circulating tumor cells (CTCs) are cancer cells that have detached from a tumor and have entered into the blood circulation at a very low concentration (D. Shook, Mech. Dev., Nov 2003). CTCs have a strong prognostic value, as their number has been correlated to overall survival in different metastatic cancers (J. S. de Bono, Clin. Cancer Res., Oct 2008). Considering the rareness of CTCs in blood, capturing them in vitro is very challenging. CTCs being mainly larger and less deformable than most of blood cells, ISET was the first system exploiting their physical traits using a filtration membrane to enrich 10mL blood samples (G. Vona, Am. J. Pathol., Jan 2000). However, placing the trapping system directly within the bloodstream would increase the amount of blood screened and ensure no sampling bias. To our knowledge, the only system developed for in vivo capture of CTCs relies on an immunologic detection targeting CTCs with specific epithelial-cell adhesion molecules (N. Saucedo-Zeni, Int. J. Oncol., Oct 2012). The major drawback of this technique is the selection bias induced, given the strong heterogeneity of antigen expression profiles in CTC population as confirmed by several studies. Methods: Our device combines the advantages of in vivo capture and physical trapping of CTCs. A polymeric 3D net-like microdevice is fabricated using a Direct Laser Writing technique (Nanoscribe) and integrated onto a Nitinol guidewire to be introduced into the basilic vein through a routine 20G catheter. To optimize the design, we conducted simulation studies and in vitro assays using a fluidic platform reproducing in vivo conditions. Results: We succeeded in capturing PC3 human prostate cancer cells from 20 mL healthy donor blood spiked with 1,000 PC3 cells in 2 minutes, demonstrating the capability to capture CTCs in conditions close to those found in vivo, in terms of pressure and flow rate and without any additional treatment or dilution of the blood. Conclusions: This device could facilitate treatment personalization and follow-up. Its versatility should render it transposable to the capture of single or clustered CTCs, derived from all types of cancer and, by extension, to other circulating cellular and molecular biomarkers.
Physiological evidence of DNA damage by carcinogens known to be present in charred and processed meats (PhIP DNA adducts) in a small cohort of patients with prostate cancer.
Authors: Weight Christopher J. , Xiao Shun , Guo Jingshu , Hwa Byeong , Villalta Peter , Tejpaul Resha , Krishna Suprita , Murugan Paari , Turesky Robert
Published: March 2017

e580

Background: Epidemiologic studies have reported an association between frequent consumption of well-done cooked meats and prostate cancer (PC) risk. Charred red meat and cooked processed meats are known to contain heterocyclic aromatic amine (HAA) carcinogens, such as 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) the most mass abundant HAA, and are linked to PC development in a rodent model. However, unambiguous physiochemical markers of DNA damage from these meat-derived carcinogens have not been identified in human samples to support the paradigm of HAA induced human prostate carcinogenesis. Methods: Thirty-five men with biopsy proven intermediate to high-risk PC underwent radical prostatectomy at University of Minnesota from Dec 2015-Aug 2016. After prostatectomy, both tumor bearing tissue and non-tumor bearing adjacent fresh tissue was analyzed for DNA adducts using a highly sensitive nano-LC-Orbitrap mass spectrometry method. We also analyzed formalin fixed paraffin embedded (FFPE) tissues from each patient. Results: Median age of the men with PC was 65 (range 45-78). Pathology demonstrated the following Gleason Scores (GS) and pathologic staging: GS = 6 in 1 patient (2.8%), GS = 7 in 28 patients (80%) and GS = 8-10 in 6 patients (17%) and 16 men (46%) were stage 2 and 19 men were stage 3 (54%). The PhIP DNA adduct was identified in 11 out of 35 patients, at levels ranging from 2 to 120 adducts per 109 nucleotides. PhIP DNA adducts also were recovered quantitatively from FFPE tissues. Conclusions: Our data provide support to the epidemiological observations implicating PhIP as a DNA damaging agent that may contribute to the etiology of PC in humans. FFPE tissues can be used as a tissue source in DNA-adduct biomarker research using our mass spectrometry method
Prevalence of oligoprogressive, metastatic castration-resistant prostate cancer (mCRPC) amenable to stereotactic ablative radiotherapy (SABR) in men undergoing abiraterone acetate (AA) therapy.
Authors: McDonald Erica , Cheng Sierra , Arciero Vanessa S. , Saluja Ronak , Zukotynski Katherine A. , Cheung Patrick , Emmenegger Urban
Published: March 2017

e587

Background: SABR is increasingly used for the treatment of men with oligometastatic prostate cancer, including patients (pts) presenting with oligoprogression. The latter is a clinical situation where a limited number of metastatic tumor sites progress (usually defined as ≤ 3-5), while all other metastases are controlled by a given systemic therapy. The frequency of oligoprogression potentially amenable to SABR is unknown. Methods: Thus, in a retrospective chart analysis we studied the progression pattern of 35 men with chemotherapy-naïve mCRPC undergoing AA therapy, and of 20 men undergoing AA therapy after docetaxel chemotherapy. Applying RECIST1.1 and/or PCWG2 criteria, pts were considered SABR candidates if they radiologically progressed in ≤ 5 distinct metastatic locations, while all other metastases were stable or responding. Results: In chemotherapy-naïve men, pre-AA metastatic lesions were located in bone (94%), lymph nodes (49%), lungs (17%) and liver (3%), whereas progression during AA therapy occurred in bone (89%), lymph nodes (49%), lungs (14%) and liver (9%). 12 pts (34%) fulfilled the criteria of oligoprogression with a median of 2 progressive lesions/pt (range 1-5). 8 pts presented with bone progression only, 3 with nodal progression, and 1 pt with combined bone/nodal progression. Post-docetaxel pts had pre-AA metastatic lesions located in bone (75%), lymph nodes (35%), lungs (5%) and liver (5%). Progression during AA therapy occurred in bone (80%), lymph nodes (75%), lungs (20%) and liver (5%). Only 1 pt met oligoprogression criteria with a single progressive bone metastasis. Conclusions: A sizeable number of men with chemotherapy-naïve mCRPC progressing during AA therapy might be considered for SABR. By contrast, progression of post-docetaxel mCRPC treated with AA is typically widespread. Further efforts are needed to identify criteria for oligoprogressive pts most suitable for SABR with sustained benefit versus men that may progress rapidly with widespread metastases following radiotherapy.
Serial FDG-PET imaging of metastatic prostate cancers reveals intrapatient intermetastases polyclonality through same patient heterogeneous responses to systemic therapy.
Authors: Morin Fannie , Beauregard Jean-Mathieu , Bergeron Michelle , Nguilé-Makao Molière , Lacombe Louis , Fradet Vincent , Fradet Yves , Pouliot Frederic
Published: March 2017

e590

Background: Although intrapatient prostate cancer (PCa) metastasis polyclonality has been recently characterized by genomic and transcriptomic studies, systemic treatment response heterogeneity has yet to be reported or imaged. It remains unknown if polyclonal differentiation leads to heterogeneous treatment responses between metastases in a single patient undergoing therapy. Methods: Between 2010 and 2015, fifteen patients with metastatic PCa were imaged by FDG-PET/CT before and during systemic therapy, and metabolic response was recorded for individual metastatic lesions. Intermetastasis heterogeneity was defined by opposite metabolic responses of at least two metastases from the same compartment (bone or soft tissue) between the two scans. We examined intrapatient intermetastasis heterogeneity of response to systemic therapy based on the assessment of metabolic response in a total of 165 individual lesions (change in SUVmax, complete response, or new lesion). Change in total lesion glycolysis (TLG) was assessed for each patient. Biochemical response and progression-free survival (PFS) were also recorded. Results: Intrapatient intermetastasis response heterogeneity was found in 40% of cases. In univariate statistical analysis, response heterogeneity was associated with a decrease in PFS (p-value= 0.001), but not with age, CRPC status, Gleason score, PSA-DT, TLG, maximum SUVmax, or sum of SUVmax. In two cases, new metastasis and complete metastasis responses were observed in the same patients. Conclusions: Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful to identify clinical resistance earlier after therapy initiation and could also enable targeted biopsy of resistant clones for molecular analysis.