bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urinary function after image-guided intensity modulated radiation therapy (IG-IMRT) of localized prostate cancer.
Authors: Obedian Edward , Zimberg Shawn H. , Kapoor Deepak A. , Olsson Carl A. 
Published: February 2017

141 Background: Men choosing treatment for prostate cancer risk potential urinary dysfunction or incontinence. The purpose of this study was to determine the effect of high dose image-guided intensity modulated radiation therapy (IG-IMRT) on urine control and function in such men. Methods: Between March 31, 2008 and September 28, 2012, 3,602 men received high dose IG-IMRT for localized prostate cancer with sufficient data for review, including baseline and minimum 11 month follow-up evaluation of urine control and function. The latter were determined by a urinary continence grading questionnaire and the International Prostate Symptom Score (IPSS). These questionnaires were completed by all men prior to radiation (baseline) and at every follow up visit. The continence questionnaire separated patients as G0: no incontinence, G1: minimal incontinence not requiring pads, G2: incontinence requiring pads, and G3: incontinence interfering with daily life activities. Men with IPSS scores of 0 to 7 were deemed mildly, 8 to 19 moderately, and 20 to 35 severely symptomatic. Typical therapy was 8100 cGy delivered to the prostate in 45 fractions. Pelvic lymph nodes were treated in 13% (458) of the cases. Results: At baseline, incontinence grading in our 3,602 men was G0 in 3,086 (86%), G1 in 479 (13%) and G2/3 in 37 (1%) and IPSS was 0-7 in 2092 (58%), 8 to 19 in 1,276 (35%) and 20 or more in 233 (6.5%). After IG-IMRT, 2,635 (85%) of baseline GO men remained continent, 408 (13%) developed G1 incontinence and 43 (1.1%) developed G2/3 incontinence. Of 479 baseline G1 incontinent men, 259 (54%) improved to G0. Of 37 baseline G2/G3 incontinent men, 21 (57%) improved to G0/1 incontinence. In 2,092 mildly symptomatic men by IPSS (average 3.5 at baseline), there was a rise to 5.4 but 1,619 (77%) remained mildly symptomatic. In the 1,276 moderately symptomatic men at baseline the average IPSS (12) decreased to 9.8 at last follow up (p<0.001). Similarly, in the 233 severely symptomatic men at baseline the average IPSS (24) dropped to 13 at last follow up (p<0.001). Conclusions: Urinary incontinence following high dose IG-IMRT for prostate cancer is rare. IG-IMRT seems to improve some men with baseline urinary incontinence and higher IPSS scores. High dose IG-IMRT remains a good treatment option for localized prostate cancer.
PSA patterns during off-time treatment period in patients undergoing intermittent androgen deprivation: Is PSA doubling time reliable in every case?
Authors: Sanchez-Salas Rafael , Prapotnich Dominique , Ingels Alexandre , Olivier Fabien , Fhima Mehdi , Descamps Patrick , Stephane David , Secin Fernando P. , Barret Eric , Galiano Marc , Rozet Francois , Cathelineau Xavier 
Published: February 2017

150 Background: Indicators such as prostate-specific antigen (PSA) nadir after the first on-treatment period (ONTP), off-phase interval duration and PSA doubling time (PSADT) were interpreted as potentially predictive, regarding outcomes of intermittent androgen deprivation (IAD). From actual PSA measurement data recorded on patients undergoing IAD during their off-treatment period (OFTP), we conducted a systematic analysis aimed at screening indicators and finely assessing their relevance as predictive candidates. Methods: Between 1992 and 2012, 727 patients with PC were selected for IAD at our institution. Three hundred ten patients had biochemical recurrence (BCR) after local treatment, 172 showed metastatic disease. ONTP consisted of three-month dose injections of gonadatropin-releasing hormone (GnRH) agonist combined with daily oral androgen receptor antagonist. OFTP was indicated when PSA was less than 4 ng/ml. Criteria for resumption of hormonal therapy were PSA more than 20 ng/ml or clinical symptoms. We tested two basic patterns of PSA behavior-exponential and power law (a<1) and combinations of them, on 597 patients with at least one completed OFTP based on four visits or more (population of the study). Results: We identified 597 patients with a total of 1,573 OFTPs. Median follow-up was 12,2 months (3,0-132,6). Median age at initiation was 76,7 (56,7 to 88,5); 811 OFTPs (51,6%) fitted with a pure exponential (r=0,01), whereas the other part (48,4%) followed more complex patterns (power law or two-steps or linear pattern). Mean cancer specific survival duration was 77,4 months (13,5 to 179,8). 5- and 10-year PC survival rate were respectively of 89,3% and 65,2% (CI 95%). Conclusions: Some OFTPs do not present an exponential pattern behavior: logarithmic calculation of PSADT is not suitable. PSADT determination should be adapted to the nature of the OFTP pattern. Through identification and analysis of the different types of OFTP, it is expected to improve the forecast of clinical outcomes.
Does adjuvant treatment affect survival in patients with positive lymph nodes at radical prostatectomy?
Authors: Harris Catherine R. , Cary Clint , Cowan Janet E. , Cooperberg Matthew R. , Carroll Peter 
Published: February 2017

157 Background: Men who are found to have positive LN at the time of RP are at risk for worse prognosis and outcomes. Our purpose is to determine whether RT after RP has a greater survival benefit than ADT alone or surgery alone in these men. Methods: This study cohort consisted of men who had RP at the University of California, San Francisco. Men with positive pelvic LN were stratified by type of adjuvant therapy: ADT, RT with or without ADT, or RP only. T-test and chi-square were used to compare clinical and pathologic characteristics. Biochemical recurrence-free, metastatic recurrence-free, and disease-specific survival were assessed with the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression. Biochemical recurrence was defined as two consecutive prostate-specific antigen values >=0.2ng/mL. Results: Of the 1,600 men had pelvic LN dissection at time of RP, 105 had positive LN. Mean age was 61 (SD 7). Median number of LN dissected was 14 (IQR 10-21) for pN1 patients versus nine (5 to 15) for pN0, p<0.01. Median percentage of positive LN was 11% (IQR 7-17). Men with positive LN had higher clinical risk and worse pathologic grade, positive margin rates, and T-stage compared to men without positive LN, all p<0.01. Recurrence-free survival was 55% for pN1 versus 81% for pN1 at 5 years, log-rank p<0.01. Following positive LN dissection at RP, 29 men received ADT monotherapy, 43 men received RT (+/- ADT), and 33 had not yet undergone treatment after RP during a median follow up of 28 months (IQR 6 to 70). Rates of seminal vesicle invasion by treatment group were 52% for ADT, 65% for RT (+/- ADT), and 35% for RP only, p=0.03. Men who underwent ADT alone, RT (+/- ADT), and RP only had few outcome events to date and similar rates of MFS (97% versus 93% versus 92%, p=0.76) and DSS (96% vs. 100% vs. 100%, p=0.32) at 3 years. Cox regression adjusted for surgical CAPRA score also showed that MFS and DSS did not differ between ADT alone, RT (+/- ADT), and RP only groups. Conclusions: Men with positive LN at the time of RP have aggressive clinical and pathologic features. Nevertheless, metastatic recurrence-free and prostate cancer-specific survival rates 3 years after surgery remain good. Although no additional survival benefit to post-RP RT was seen in this cohort of men with limited follow up, further follow up is ongoing.
The enzymology of the selective CYP17 lyase inhibitor, VT-464, and its effects in castration-resistant prostate cancer (CRPC) models.
Authors: Moore William R. , Maity Sankar N. , Eisner Joel Robert , Garvey Edward P. , Hoekstra William J. , Titus Mark Anton , Logothetis Christopher , Araujo John C. , Efstathiou Eleni , Schotzinger Robert J. 
Published: February 2017

158 Background: CRPC typically responds to anti-androgen therapy but resistance is common. CYP17 inhibitors that block lyase (L) and not hydroxylase (H), do not require prednisone, and may delay tumor resistance are needed. VT-464 is an oral, non-steroidal inhibitor of CYP17 L in clinical development for CRPC. The present studies characterized: 1) the kinetic mechanism of VT-464 inhibition of h-CYP17 L and H, and 2) VT-464 effects compared to abiraterone acetate (AA) in CRPC models. Methods: CYP17 Enzyme Assays: r-h-CYP17 inhibition studies were conducted using substrates pregnenolone (for H) or 17-a-hydroxypregnenolone (for L). Product rates (17-a-hydroxypregnenolone (H) and DHEA (L)) were assessed by LC/MS/MS. Data were fit to inhibition models using SigmaPlot 11.2. In vitro CRPC studies: VT-464 and AA effects on AR transcription (luciferase) and PSA and NKX3.1 gene expression (QRT-PCR) were compared in C4-2B cells. Mouse xenograft model: Effects of oral VT-464 or AA on tumor growth and tumoral steroids (T, DHT, P) were compared in the MDA-PCa-133 castrate mouse model. Results: VT-464 was a reversible uncompetitive inhibitor of CYP17 L (Ki = 84 nM, K’i=200 nM) and a competitive inhibitor of H (Ki = 620 nM). VT-464 CYP17 L/H selectivity was 7.4 at low [S] but selectivity increased with increasing [S]. VT-464 L/H selectivity was 60-x greater than AA. In C4-2B cells VT-464 and AA inhibited AR transactivation but VT-464 suppressed PSA and NKX3.1 more potently than AA. In the xenograft model, VT-464 decreased tumor volume as effectively as AA. VT-464 more potently decreased T and DHT, while AA increased P. Conclusions: VT-464 demonstrated much greater CYP17 L selectivity than AA and equivalent or superior activity in several CRPC models. Less tumor resistance may arise from treatment with the CYP17 lyase-selective inhibitor VT-464 than with AA, since it more effectively blocked androgen biosynthesis, did not cause an accumulation of progesterone, and should not require co-administration of prednisone.
The effect of prostate brachytherapy technique on quality of life outcomes: 5-year outcomes of a prospective cohort study.
Authors: Talcott James Austin , Clark Jack A. , Manola Judith , Kaplan Irving D. , Zietman Anthony L. , D'Amico Anthony Victor 
Published: February 2017

166 Background: Brachytherapy (BT) is widely used to treat clinically localized prostate cancer, but techniques vary and may affect patient outcomes. Methods: We prospectively studied three Boston-area patient cohorts who received different BT techniques: MRI guided, target volume avoids transition zone (MRBT) and two cohorts using standard imaging and planning techniques (USBT1 and USBT2). We surveyed patients pretreatment and at intervals after, using the validated PCSI scales for urinary incontinence (incont), obstruction/irritation (obstir) bowel problems, sexual dysfunction and the effect of incont on their lives (incontQOL). Based on early results showing increased acute urinary toxicity, USBT2 providers adopted an element of USBT1 technique. We report final 5-year follow-up. Results: Of 286 eligible patients, 73 MRBT patients and 190 USBT patients (99 USBT1 and 91 USBT2 patients) completed at least 3-month surveys. Patient differed by age (median: MRBT 65.3 years vs. USBT 68.3 p=0.005, USBT2 65.3 vs. USBT1 68.3 p=0.004) and education (MRBT 8%≤high school vs. USBT 23%, p<0.001) but other demographic and clinical variables were similar. MRBT patients had more pretreatment obstir symptoms and better sexual function pretreatment. USBT2 patients had greater increases in acute (3-month) obstir (28.8 vs. 20.0, p=0.01) and incont (12.2 vs. 7.1, p=0.01) than USBT1 but not bowel or sexual dysfunction, and all outcomes were similar at 5 years. Changing USBT2 technique eliminated the acute urinary differences. Compared to MRBT, USBT patients had greater increases in acute urinary morbidity (obstir 28.8 vs. 20.0, p=0.01; incont 9.6 vs. 2.2, p=0.002; incontQOL 10.2 vs. 2.4, p=0.0002) and long-term incontinence (incont 7.5 vs. 3.3, p=0.05; incontQOL 5.6 vs. 1.2, p=0.01). Other outcomes did not differ. Conclusions: QOL outcomes vary by BT technique. Measuring QOL may provide useful information for patients choosing treatment and providers assessing their technique. Clinical trial information: NCT00681694.
Prostatectomy at high- versus low-volume centers: A decision analysis.
Authors: Barzi Afsaneh , Klein Eric A. , Dorff Tanya B. , Quinn David I. , Sadeghi Sarmad 
Published: February 2017

175 Background: Greater experience improves the oncological outcomes of radical prostatectomy (RP) for prostate cancer; however, it is not clear whether referring patients to a high volume center (HVC) for RP is cost effective. This study aims to investigate this question. Methods: We assumed status quo wherein 50% of RPs occur at an HVC and the other 50% occur in less experienced hands (scenario one or “referent scenario”). We then modeled increasing the share of RPs at an HVC by 10% increments (scenarios two, three, and four). Assuming that a lower probability of prostate-specific antigen recurrence (PSAR) is the only advantage of more experienced surgeons, the savings that would result from fewer recurrences, avoidance of salvage radiation therapy (SRT) and management of fewer men with metastatic cancer were calculated. A breakeven analysis using incremental referral costs and a cost effectiveness analysis (CEA), adding the incremental effectiveness measured in years in the no evidence disease (NED) state and the expected difference in overall survival (OS), were performed to determine the breakeven point and the range of the maximum referral costs to an HVC. Results: At five years 8.2% of patients will experience PSAR in the referent scenario versus 6.9% in scenario four. More patients would have PSAR in a low-volume center (LVC) setting after RP. Assuming 37% of these patients would receive SRT and those who will develop metastatic disease will receive treatment, this incremental cost discounted at 3% is $265, $456, and $609 per RP for scenario four at 5, 10, and 15 years, respectively. These figures will be $177, $309, and $415 and $86, $152, and $205 at 5, 10, and 15 years for scenarios three and two, repectively. Breakeven analysis shows that over 15 years, savings from referring patients to an HVC would offset up to $2,000 per RP in initial referral costs. This figure remains stable for scenarios two, three, and four. CEA shows that the range for maximum costs of referral assuming a willingness to pay of $50,000 per year are $4,300 to $23,700 at 15 years of follow up. Lower PSAR rates for LVCs, or using the lower SRT or treatment of metastasis costs result in smaller values for breakeven referral costs. Conclusions: Performing RPs at an HVC is associated with significant savings that offset the initial referral costs and may be cost effective beyond the breakeven point.
The effect of prior abiraterone (Abi) use on the activity of enzalutamide (Enza) in men with mCRPC.
Authors: Cheng Heather H. , Nadal Rosa , Gulati Roman , Azad Arun , Twardowski Przemyslaw , Vaishampayan Ulka N. , Agarwal Neeraj , Heath Elisabeth I. , Pal Sumanta Kumar , Rehman Hibba-tul , Leiter Amanda , Batten Julia Anne , Montgomery Robert B. , Galsky Matt D. , Chi Kim N. , Antonarakis Emmanuel S. , Yu Evan Y. 
Published: February 2017

18 Background: Enzalutamide (Enza) and abiraterone (Abi) are next generation hormonal agents for metastatic castration resistant prostate cancer (mCRPC). Whether these agents can be effectively sequenced is not yet well understood. Results of retrospective analyses of Abi after prior Enza have demonstrated modest responses of brief duration, suggesting common resistance pathways. Here, we retrospectively analyze response to Enza with or without prior Abi treatment. Methods: We retrospectively reviewed 195 patients from seven academic centers treated with Enza between January 2009 and August 2013. Data were collected on disease characteristics, prior therapies, and prostate-specific antigen (PSA) values at baseline and while on treatment. Logistic regression was used to evaluate association between 30% or greater PSA decline on Enza and either prior Abi treatment or 30% or greater PSA decline on prior Abi after accounting for potential confounders. Results: One hudred eighty three patients had non-missing PSA starting and nadir values on Enza, with starting PSA median 102.0 (range 1.1–5007.0) ng/mL. Overall, 42% (76 of 183) of Enza-treated patients achieved a 30% or greater PSA decline, with 39% (58 of 150) response among prior Abi-treated patients and 55% (18 of 33) response among Abi-naïve patients. Of 79 patients who lacked significant response to prior Abi, 30% (25 of 79) achieved a 30% or greater PSA decline and 19% (15 of 79) achieved a 50% or greater PSA decline with subsequent Enza. Odds of achieving a 30% or greater PSA response on Enza was 2.3 times higher for Abi-naïve patients versus prior Abi-treated patients (95% CI 1.0–5.5, P=0.06) and 1.9 times higher for Abi-responders vs Abi-non-responders (95% CI 1.0–3.7, P=0.06) after adjusting for prior docetaxel and concurrent steroid use. Conclusions: In this multi-center retrospective study, 39% of patients achieved a 30% or greater PSA decline with Enza after prior Abi treatment. While the activity of Enza appears to be blunted in the post-Abi setting, PSA declines still occur in a meaningful proportion of patients. Notably, 30% of patients without significant response to prior Abi responded to subsequent treatment with Enza, suggesting a subset of men with distinct biological resistance pathways. Data will be updated at the time of presentation.
Diagnostic value of biparametric MRI as an adjunct to PSA-based detection of prostate cancer.
Authors: Rais-Bahrami Soroush , Siddiqui Minhaj , Vourganti Srinivas , Turkbey Baris , Rastinehad Ardeshir , Stamatakis Lambros , Truong Hong , Walton-Diaz Annerleim , Hoang Anthony N. , Nix Jeffrey , Merino Maria , Wood Bradford J. , Simon Richard , Choyke Peter L. , Pinto Peter A. 
Published: February 2017

193 Background: To determine the diagnostic yield of analyzing a fast, cost-conscious biparametric (T2 and diffusion-weighted) MRI (B-MRI) for prostate cancer (PCa) detection as an adjunct to to standard digital rectal exam (DRE) and prostate specific antigen (PSA)-based screening. Methods: Review of patients who were enrolled in a trial to undergo MP-MRI and MR/US fusion-guided prostate biopsy at our institution identified 143 men who underwent MP-MRI in addition to standard DRE and PSA-based PCa screening prior to any other prior prostate biopsy sessions. Patient demographics, DRE staging, PSA, PSA density (PSAD), and B-MRI findings were assessed for association with PCa detection on biopsy. Results: Men with detected PCa tended to be older, with higher PSA, higher PSAD, and increased number of screen positive lesions (#SPL) on B-MRI. B-MRI performed well for the detection of PCa with an area under the curve (AUC) of 0.80 (compared to 0.66 and 0.74 for PSA and PSAD). We derived PSA and MRI-based combined screening formulas for detection of PCa with optimized thresholds. (1) for PSA and B-MRI: PSA + 6 x (#SPL) > 14 and (2) for PSAD and B-MRI: 14 x (PSAD) + (#SPL) > 4.25. Area under the curve for equations 1 and 2 were 0.83 and 0.87 and overall accuracy of PCa detection was 79% in both models. Furthermore, the model integrating PSA with #SPL on B-MRI, was much more efficient at maximally identifying men with Gleason 7 or higher disease compared to PSA-screening alone. Use of model combining PSAD and MRI, the number of bGS 7 or higher cancers that were missed was minimized. Overall, combined use of PSA or PSAD coupled with B-MRI #SPL improved the true positive yield of identifying men with bGS 7 or higher while minimizing the false positive number of men identified as “screen-positive,” but with no cancer on biopsy. Conclusions: Number of positive lesions on B-MRI outperforms PSA alone in detecting PCa, supporting the use of this limited, non-contrast MRI as a potential adjunct tool in PCa screening. Furthermore, this imaging criteria coupled as an adjunct with PSA and PSAD, provides even more accuracy in detecting clinically-significant PCa.
Epigenetic profiling of prostate cancer tissue to identify men with high-risk disease.
Authors: Van Neste Leander , Falk Jeffrey , Lee Ming-Chou , Bigley Joseph , Van Criekinge Wim , Crawford E. David 
Published: February 2017

197 Background: Prostate cancer (PCa) prognosis and aggressiveness are guided by Gleason Scores (GS). Moreover, biopsied prostate tissue might not be representative of the actual disease. Epigenetics could provide a quantitative method for confirming or upgrading disease status obtained by GS, providing additional information with regard to aggressiveness. Methods: Eighty-four prostatectomy samples from PCa patients with GS6 (n=6), GS3+4 (n=41), GS4+3 (n=26) and GS greater than or equal to 8 (n=11) were epigenetically profiled, for GSTP1, APC, RASSF1, RARB, and GAL3 methylation, using methylation-specific PCR. Unsupervised hierarchical clustering, based on Ward’s method, was performed to discover an association between DNA-methylation patterns and GS. Methylation ratios were scaled across all samples by calculating, per gene, a Z-score. Results: Hierarchical clustering analysis resulted in three distinct clusters. One cluster with a relative, general depletion of methylation, a second cluster with high methylation levels for most genes, particularly for RARB, and a third cluster exhibiting intermediate methylation signals and lower, but distinct, RARB methylation. Kendall’s rank correlation tau indicated a significant positive correlation between GS and methylation levels of all five genes, with tau ranging from 0.010 to 0.376 (all p values<0.05). Methylation levels of all five genes were significantly lower in the samples with GS less than or equal to 3+4 versus those with GS greater than or equal to 4+3 (all p values<0.05). Clustering showed that 100% of the GS6 and 80% of the GS3+4 patient’ samples were associated with low methylation signals. In contrast, 81% and 82% of the GS4+3, and GS greater than or equal to 8 samples respectively, fell into the category with intermediate to high methylation levels. Conclusions: Methylation levels of all genes correlated with GS and were significantly lower in patient' samples with GS6 and GS7 (3+4) compared to GS7 (4+3) and GS greater than or equal to 8. This study shows that epigenetic profiling of selected genes has prognostic value and may help to identify patients with aggressive PCa.