bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall survival beyond first-line docetaxel in patients with metastatic castrate-resistant prostate cancer treated with abiraterone acetate or enzalutamide.
Authors: Heo Mi Hwa , Park Se Hoon , Kim Hee Kyung , Cho Jinhyun , Kim Youjin , Lee Hansang
Published: March 2017

e570

Background: In post-docetaxel setting of metastatic castrate-resistant prostate cancer (mCRPC), survival benefit with abiraterone acetate or enzalutamide is well established. This retrospective study was performed with the data obtained our cancer chemotherapy registry to evaluate real-world mCRPC patient outcomes. Methods: All consecutive patients treated with either abiraterone acetate or enzalutamide in post-docetaxel setting between 2013 and 2014 were included. The decision for administering second-line agents was, in most cases, at the discretion of the treating oncologists. The primary endpoint of this study was overall survival (OS), and the secondary endpoints included safety, prostate-specific antigen (PSA) response ( ≥ 50% decline) and progression-free survival (PFS). Univariate and multivariate analyses for OS were performed on the recognized baseline parameters and therapy. Results: A total of 54 eligible mCRPC patients received either abiraterone acetate (n = 25) or enzalutamide (n = 29). At the time of commencing second-line therapy, the patients’ median age was 70 years (range, 45-86) and 30 patients (56%) had a symptomatic disease. Visceral disease was present in 12 patients, and 12 had bone-only metastasis. Both were well-tolerated without significant toxicities. PSA response was observed in 36% and 52% for abiraterone acetate and enzalutamide, respectively. The estimated median PFS and OS were 5 and 15 months, respectively. Multivariate analysis revealed that the presence of clinical symptoms was the only independent prognostic factor for OS. Conclusions: Within the limitation of small sample size, the results are consistent with existing literature suggesting that both abiraterone acetate and enzalutamide appear to be effective as second-line therapy for docetaxel-pretreated mCRPC.
Heterogeneous populations driven by clinical practice: A case example comparing enzalutamide (ENZA) and bicalutamide (BIC).
Authors: Kim Ruth , Brookhart M. Alan , Flanders Scott , Schultz Neil M. , Fryzek Jon , Barlev Arie
Published: March 2017

e571

Background: Comparative real-world insurance claims data (RWD) analysis can be used to compare homogeneous cohorts (to avoid selection bias). Since the National Comprehensive Cancer Network guidelines recommend ENZA for metastatic castration-resistant prostate cancer (PC) and BIC for localized PC, it was of interest to evaluate these 2 heterogeneous cohorts as the ENZA cohort, being further advanced in the disease, has a worse prognosis than the BIC cohort. Here, we describe the results of a post hoc analysis on the ENZA and BIC cohorts to confirm the heterogeneity of demographics presented in a published study (Behl A et al. J Clin Oncol. 2016;34:235). Methods: The RWD captured enrollees with PC, claims for ENZA or BIC from 09/01/2012–12/31/2014, and at least 6 mo of continuous enrollment prior to the index date. After replicating methods from Behl et al using Truvan, we explored the balance of demographics in baseline periods greater than 6 mo. Differences in demographics and the post hoc analysis were compared. Results: Behl et al reported balanced age between the ENZA (73.1±10.0 y) and BIC (71.4±10.5 y) cohorts. However, 90% (531/592) of the ENZA cohort were metastatic vs 35% (1917/5524) of the BIC cohort. The Quan-Charlson comorbidity index was higher for the ENZA (5.6±2.1 y) than BIC (3.2±2.1 y) cohort. In the ENZA cohort, abiraterone acetate (ABI) or BIC utilization in the baseline period was higher (53%) than in the BIC cohort (0%). When the baseline period was greater than 6 mo, per our post hoc analysis, prior use of ABI or BIC increased to 68% for the ENZA cohort and remained unchanged in the BIC cohort. Conclusions: Despite results from the Behl analysis, the ENZA and BIC cohorts were dissimilar; ENZA patients had more advanced disease (metastatic disease; received ≥ 1 therapy) than BIC patients. Comparison of such heterogeneous populations can lead to biased estimates of treatment effects. Analyses lacking appropriate measures of prognostic variables that guide treatment decisions should be cautiously interpreted. Further analysis is required to identify best practices for using RWD and to address confounding driven by clinical practice.
Early assessment of PSA response in patients with mCRPC treated with enzalutamide and abiraterone.
Authors: Feibus Allison H. , Guccione Jeffrey R. , Vasudevamurthy Ashwin , Ledet Elisa M. , Cotogno Patrick , Manogue Charlotte , Ernst Emma M. , Lewis Brian E. , Silberstein Jonathan L. , Sartor A. Oliver
Published: March 2017

e574

Background: Abiraterone (Abi) and enzaleutamide (Enza) are first-line agents for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Primary resistance is well-documented, but little data exists for rapid treatment responders. This study intended to further characterize patients with early prostate-specific antigen (PSA) decline. Methods: A single-institution retrospective review was performed on 123 mCRPC patients treated with Abi and/or Enza. PSA was recorded every 4 weeks for the duration of treatment. The primary endpoint was to describe PSA response, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥50% decrease in PSA from baseline). Additional clinical covariates were also evaluated as treatment-response predictors. Results: A PSA response to Abi was achieved in 52/123 (42%) of patients. Median time to PSA nadir was 37 days. 30/52 (58%) patients responded to the drug within 4 weeks. Median length of time on drug was 110 days. A PSA response to Enza was achieved in 21/123 (17%) of patients. Median time to PSA nadir was 140 days. 18/21 (86%) of patients responded to the drug within 4 weeks. Median length of time on drug was 161 days. Conclusions: Percentage of PSA decline and time to drug response for Enza and Abi are important variables that can serve as reliable way for clinicians to predict long-term PSA response. It is vital to make appropriate treatment modifications for patients that do not display early PSA response. [Table: see text]
Association between primary surgery and all-cause mortality among elderly patients with high-risk prostate cancer.
Authors: Chhatre Sumedha , Lee David Inkoo , Yu Doyeong , Malkowicz S. Bruce , Jayadevappa Ravishankar
Published: March 2017

e576

Background: To determine the five year survival impact of primary surgery compared to radiation therapy in older men with high risk prostate cancer. Methods: This was a population-based cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare patients 66 years or older, diagnosed for prostate cancer between 2004 and 2008. High-risk prostate cancer was identified as Gleason score of ≥ 8, or clinical stage T3a. Treatments studied were definitive local (curative intent) therapy (surgery or radiation therapy) within 180 days of prostate cancer diagnosis. The two treatment groups were retrospectively followed for one-year pre and five years post diagnosis. Main outcome measure was five-year all-cause mortality and cancer specific mortality. Sequential Cox regression was used to assess the hazard of mortality associated with surgery, compared to radiation therapy, after adjusting for socio-demographic variables, variables and propensity score. Results: We identified a cohort of 24,838 men newly diagnosed for high-risk for prostate cancer between 2004 and 2008. Forty-seven percent of these had surgery (n = 11,696) as well as radiation therapy (n = 11,724) as a primary treatment with curative intent within 180 days of diagnosis. Mean age at diagnosis of radiation therapy group was higher compared to surgery group (73.5, sd = 5.3 vs. 70.3, sd = 4.9; p = 0.020). Radiation group had higher comorbidity compared to surgery group (37% vs. 26%, p = 0.0316). Unadjusted all-cause mortality comparison over five years of follow-up showed that surgery treatment was associated with lower mortality (HR = 0.58, CI = 0.54, 0.62). After adjusting for propensity score, the hazard of all-cause five year mortality remained lower for surgery compared to radiation therapy (HR = 0.86, CI = 0.78, 9.4). Conclusions: Over a five-year follow-up, primary surgery was associated with improved survival compared to radiation therapy in high-risk prostate cancer patients. Longer follow-up is needed to determine if the survival advantage of surgery will persist as well as factors contributing to the difference in survival.
Interim analysis of NCT02458716: Feasibility of cytoreductive prostatectomy in men newly diagnosed with metastatic prostate cancer.
Authors: Yuh Bertram E. , Kwon Young Suk , Shinder Brian , Kim Sinae , Lee Nara , Ruel Nora , Kim Isaac Yi
Published: March 2017

e578

Background: Emerging evidence has suggested that local tumor control may enhance the effect of subsequent therapies in patients with metastatic prostate cancer. However, little is known about surgical safety of cytoreductive prostatectomy (CRP). In this study, we report the first interim analysis of a phase I study evaluating the safety and feasibility of CRP. Methods: The study was approved by the IRB and activated in June, 2015. Individuals with newly diagnosed clinical metastatic prostate cancer to lymph node or bones (cT1-3N1M0 or cT1-3N0M1a-b) were recruited. Following surgery, all patients received androgen deprivation therapy. The primary endpoint is the major complication rate (Clavien ≥ III). The secondary outcome measures are the time to PSA nadir and rate of incontinence (pad-free). Results: A total of 20 men from two institutions have been enrolled and undergone CRP. Overall, 6 (35.3%) perioperative complications were observed, including 1 major complication (Clavien ≥ III). There were 5 minor complications, including deep venous thrombus (Clavien II), postoperative ileus (Clavien II), and 3 cases of urethral anastomotic leaks (Clavien I). In men with a minimum of 6 month follow-up, PSA < 0.2 ng/ml in 63.6% of men and 50% of men were pad free. Conclusions: CRP is surgically feasible in carefully selected patients. However, early incontinence rate is high. Further studies are warranted to further define long-term complications and verify the oncologic benefits of the surgery. Clinical trial information: NCT02458716. [Table: see text]
Antitumor activity of abiraterone, enzalutamide, and docetaxel following treatment with diethystilbestrol in castration-resistant prostate cancer.
Authors: Assoun Sandra , Campedel Luca , Roupret Morgan , Vaessen Christophe , Parra Jerome , Boostandoost Haide Angele , Comperat Eva , Simon Jean-Marc , Khayat David , Bitker Marc-Olivier , Malouf Gabriel G. , Spano Jean-PHilippe
Published: March 2017

e581

Background: Docetaxel and Next-Generation Anti-Androgens (NGAA) including abiraterone and enzalutamide represent the standard of treatment for patients with castration-resistant prostate cancer (CRPC). Treatment sequencing of these agents is a challenge. Recent studies identified cross-resistances between hormonal therapies and taxanes, as well as between different NGAA. In aiming to elucidate whether synthetic oestrogen diethylstilbestrol (DES) therapy impacts the efficacy of later-line treatments or not, we evaluated the antitumor activity of NGAA and docetaxel following DES therapy in CRPC patients. Methods: All patients with CRPC treated at Pitié-Salpêtrière hospital in first-line setting with DES from September 1995 to July 2016 were retrospectively identified. We evaluated further activities of abiraterone, enzalutamide and docetaxel in those patients after DES therapy, using Prostate Cancer Working Group 3 criteria. Clinicopathologic characteristics, including age, performans status, metastatic sites at diagnosis and treatments initiation, and data survival were also assessed. Results: Twenty-three patients with CRPC were initially treated with DES with a median time to prostate-specific antigen (PSA) progression of 9.7 months (range, 4.7-20.3). Thirteen patients(56.5%) received abiraterone or enzalutamide before docetaxel and 21 patients (91.3%) after. Median age at first NGAA initiation was 79 years) range, 55-91). Only one patient (7.7%) achieved a PSA decline before docetaxel and two out of 18 evaluable patients (11.1%) after docetaxel. Median time to PSA progression and overall survival with a NGAA treatment were respectively 2.8 (range, 2.0-4.1) and 16.5 months(range, 4.3-31.0). Fifty percent of patients showed a PSA response with docetaxel. No clinical factors were found to be significantly associated with PSA response to NGAA treatment, nor to docetaxel. Conclusions: The activity of NGAA appears markedly limited after a DES therapy, regardless of the PSA response to docetaxel. These data suggest the likelihood of a cross-resistance mechanism between DES and NGAA, without no impact on taxanes pathways.
Head-to-head pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprorelin acetate formulations in male patients.
Authors: Moul Judd W. , McLane John A. , Atkinson Stuart , Concepcion Raoul S.
Published: March 2017

e589

Background: Leuprolide acetate (LA) is the standard-of-care luteinizing hormone-releasing hormone (LHRH) agonist used to suppress serum testosterone (T) in the treatment of advanced prostate cancer. There are currently two LA formulations available: a controlled-release implant injected subcutaneously (SC) or a microsphere intra-muscular (IM) injection. The study compared the pharmacokinetics/pharmacodynamics of both formulations at the same one-month dose. Methods: Thirty-two healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase 1, open-label, parallel-group study. Serum LA, T, and luteinizing hormone (LH) were assessed. Results: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27±4.9 vs. 19±8.0 ng/mL, respectively), with a shorter tmax (1.0±0.4 vs. 2.1±0.8 hrs). Mean serum LA remained above the level of quantification (LOQ, 50 pg/mL) through Day 49 for SC-LA, whereas for IM-LA, mean serum LA dropped below the LOQ after Day 28. Median LH concentration remained low at Day 56 in the SC-LA group, whereas LH levels began to rise after Day 35 in the IM-LA group. Consequently, serum T began to increase by Day 42 in the IM-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ≤ 50 ng/dL vs. 0 in the IM-LA group. Both SC-LA and IM-LA were well tolerated, however SC-LA subjects experienced more mild injection site disorders compared to IM-LA. Conclusions: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27±4.9 vs. 19±8.0 ng/mL, respectively), with a shorter tmax (1.0±0.4 vs. 2.1±0.8 hrs). Mean serum LA remained above the level of quantification (LOQ, 50 pg/mL) through Day 49 for SC-LA, whereas for IM-LA, mean serum LA dropped below the LOQ after Day 28. Median LH concentration remained low at Day 56 in the SC-LA group, whereas LH levels began to rise after Day 35 in the IM-LA group. Consequently, serum T began to increase by Day 42 in the IM-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ≤ 50 ng/dL vs. 0 in the IM-LA group. Both SC-LA and IM-LA were well tolerated, however SC-LA subjects experienced more mild injection site disorders compared to IM-LA.
Polymer delivered, subcutaneously administered leuprolide acetate provides stable and long-term drug delivery and testosterone suppression in 4 pivotal trials.
Authors: Chu Franklin , Atkinson Stuart , McLane John A. , Kassabian Vahan
Published: March 2017

e592

Background: Prostate cancer patients receive androgen deprivation therapy (ADT) to suppress testosterone (T) to prevent proliferation of cancer cells. T suppression levels achieved by bilateral orchiectomy remain the gold standard for the target of suppression by ADT. Although the historical threshold definition of castration is T ≤ 50 ng/dL, increasing evidence suggests T lower than 20ng/dL may improve clinical outcomes, e.g., an increased cancer specific survival and delayed disease progression. To determine the minimal threshold of serum leuprolide required to maintain castrate level T suppression in prostate cancer patients, data from 4 pivotal trials evaluating long-acting, subcutaneously (SC) administered leuprolide acetate (LA) formulated with a biodegradable polymer were pooled. Methods: 438 eugonadal prostate cancer patients (age 40-86) were treated with SC-LA at 7.5, 22.5, 30, or 45mg delivered with a single dose lasting over 1, 3, 4, or 6 months (n = 120, 117, 90, 111), respectively in 4 open-label, fixed-dose, pivotal trials. Descriptive statistics were used to summarize the median concentration of leuprolide acetate at each time point as well as to determine level of T suppression. Results: Over the dosing intervals of the 1, 3, 4 and 6-month SC-LA formulations, median serum leuprolide levels were consistent and median serum T remained below T < 20 ng/dL. In the pooled analysis (n = 86), 99% of patients with LA ≥ 0.1 ng/mL after injection achieved castration after 4 Weeks. Conclusions: These data suggest that SC-LA achieves consistent and prolonged drug delivery resulting in sufficient serum LA levels to provide favorable T suppression below 20 ng/dL, which may have clinical outcomes, e.g., increased cancer specific and progression free survival.
Evaluating the effect of therapy duration on survival in patients with metastatic castration-resistant prostate cancer receiving radium-223.
Authors: Williams Noelle L. , Nowak-Choi Kamila , Skowronski Jenna , Dan Tu , Eldredge Harriet Belding , Hoffman-Censits Jean H. , Lin Jianqing , Kelly William Kevin , Gomella Leonard G. , Lallas Costas D. , Trabulsi Edouard John , Hurwitz Mark , Dicker Adam , Leiby Benjamin E. , Dabbish Nooreen , Den Robert B.
Published: March 2017

e593

Background: The use of radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC) improves overall survival (OS) and quality of life. Combination of radium-223 with second-generation anti-androgens has further improved OS; however, the optimal length of radium-223 treatment for maximal effect remains unknown. Methods: We reviewed 35 consecutive patients with mCRPC who received radium-223 from December 2012 to August 2015 at Thomas Jefferson University. Patients were divided into two groups: those who received full treatment of 6 injections (n = 18) versus those who received less than 6 injections (n = 17). Kaplan-Meier analysis of OS were tested for difference by treatment group using Log Rank test. Univariable association with survival outcomes was calculated with univariable Cox regression and Log Rank tests. Results: Mean age was 73 ± 10 years and Karnofsky performance status (KPS) ranged from 50-90 (median, 80). Median follow-up was 13.9 months. Eighteen patients were receiving concurrent second generation anti-androgens at the start of treatment. Median OS was 12 months for patients who received 6 injections and 6.48 months for patients who received less than 6 injections (p = 0.0045). The results of univariate Cox regression analysis revealed full treatment was associated with increased OS (p = 0.0013). On multivariate analysis accounting for KPS, full treatment was significantly associated with improved OS (p = 0.0028). Conclusions: In this retrospective, single-institution analysis, we demonstrated that full course completion of radium-223 was associated with improved OS in patients with mCRPC. These patients should be optimally supported during treatment to allow for therapy completion.
The impact of multifocal perineural invasion on biochemical recurrence and timing of adjuvant androgen-deprivation therapy in high-risk prostate cancer following radical prostatectomy.
Authors: Shen Pengfei , Sun Guangxi , Zeng Hao , Zhang Xingming
Published: March 2017

e595

Background: Perineural invasion (PNI) is a distinct pathologic entity and a recognized source of tumor spread. However, the role of PNI in high-risk prostate cancer (PCa) has not been explored. We investigated the impact of the severity of PNI on biochemical recurrence (BCR) and optimal timing of adjuvant androgen deprivation therapy (ADT) post radical prostatectomy (RP). Methods: Of 265 prostatectomies, median follow-up 45 months, were assessed for the presence of PNI and its intensity (unifocal PNI and multifocal PNI) in RP specimen. Kaplan-Merier curves were used to estimate BCR probabilities. Cox proportional hazard models were used to address predictors of BCR. Harrell’s C-index was conducted to further validate prognostic value of multi-PNI. Results: A total of 123 patients (46.4%) were PNI positive, among which, 91 (74%) and 32 (26%) had unifocal PNI (uni-PNI) and multifocal PNI (multi-PNI), respectively. Other than uni-PNI, the presence of multi-PNI was strongly associated with increasing incidence of BCR (HR = 3.87, 95% CI: 1.66-9.01, p = 0.002). Patients with uni-PNI seemed to have a similar BCR rate to those without PNI after adjuvant ADT. For men with multi-PNI, immediate ADT obviously appeared to be superior to delayed ADT in decreasing biochemical failure. Conclusions: Multi-PNI detected in high-risk RP specimens could be a prognosticator for early biochemical relapse post-surgery. Our findings suggest that patients with multi-PNI appear appropriate to choose adjuvant therapy as soon as possible after surgery.
Changes in hormonal therapy during the first 24 months of treatment: A longitudinal cohort study.
Authors: Lebret Thierry , Rossi Dominique , Zerbib Marc , Moreau Jean Luc , Ruffion Alain , Neuzillet Yann , Hennequin Christophe
Published: March 2017

e599

Background: Data are limited showing changes in patients’ use of androgen deprivation therapy (ADT) in routine clinical practice. Methods: In this non-interventional, longitudinal cohort study, we assessed the number and type of modifications of ADT during the first 24 months of treatment in France. At baseline and every 6 months, we collected clinical, biological and therapeutic data and any changes of ADT modality. Results: Between July 2011 and January 2015, 891 pts were evaluable at 24 months. Mean age was 74.1±8.7 years. Indications for ADT were: biochemical relapse after local treatment (21.4%), adjuvant to radiotherapy (RT) (31.6%), metastases (24.2%) and locally advanced tumor without local treatment (20.6%). Gleason score was > 7, 7(4+3), 7 (3+4) and < 7 in 33.6%, 23.1%, 26% and 17.3%, respectively. At 24 months, modification of ADT was reported in 390 pts (43.8%). Modifications of ADT according to indications are summarized in table below. The main types of modification concerned the formulation (molecule or duration of action) (61.3%), duration of ADT (10.5%), switch to intermittent treatment (10.0%), addition of chemotherapy (5.6%) or second line hormonal manipulation (9.0%). Clear explanation for adaptations was given for only 110 patients: disease progression: 55.5% ; patient request: 26.4%, tolerance: 12.7% and failure of castration: 7.3%. Conclusions: Change of initial modality of ADT is frequent in the first 24 months of treatment (43.8%) and numerically more frequent in presence of metastases or biochemical relapse than when ADT is added to RT. Surprisingly, the main type of modification is formulation. The main reason for modification is disease progression. [Table: see text]
The prognostic role of IDC-P in mCRPC and its predictive value in those treated with docetaxel or abiraterone as first-line therapy.
Authors: Zhao Jinge , Zeng Hao , Shen Pengfei , Sun Guangxi , Liu Jiandong , Zhang Xingming , Chen Zhibin
Published: March 2017

e603

Background: Intraductal carcinoma of prostate (IDC-P) is recognized as a newly pathological entity in 2016. Its role in metastatic castration-resistant prostate cancer (mCRPC) remains unknown. The aim of this study is to explore the association of IDC-P with clinical outcomes and to further identify its potential predictive role in making first-line treatment decision for mCRPC patients. Methods: We retrospectively analyzed data of 131 men with mCRPC. IDC-P was diagnosed by re-biopsy at the time of mCRPC. After mCRPC, 45 and 41 patients received abiraterone (Abi) or docetaxel (Doc) as first-line therapy, respectively. PSA response, PSA progression-free survival (PSA-PFS) and overall survival (OS) from mCRPC to death were analyzed. Kaplan-Meier curves, log-rank test, Cox regression models and Harrell’s C-index were conducted to analyze disease progression, treatment efficacy and outcomes. Results: The incidence of IDC-P in mCRPC reached to 47.3%. IDC-P was not only related to rapid PSA progression, but also associated with 20-month decrease of OS. Among IDC-P(-) patients, PSA response, PSA-PFS and OS were comparable in Abi-treated and Doc-treated groups. In contrast, among IDC-P(+) patients, PSA response rate is higher in Abi-treated vs. Doc-treated group (52.4% vs. 21.7%; p = 0.035), also, PSA-PFS and OS were much longer in Abi-treated group (PSA-PFS:13.5 vs.6.0 months, p = 0.012; OS:23.6 vs.14.7 months, p = 0.128). Cox regression indicated that, for IDC-P(+) patients, Abi was associated with prolonged time of PSA-PFS (HR = 0.33, 95%CI: 0.14-0.79, p = 0.013), and could significantly increase the predictive accuracy of standard model, with an obvious increase of the C-index from 0.719 to 0.778 (p = 0.009). Conclusions: The presence of IDC-P in mCRPC from re-biopsy was not only an independent prognosticator for clinical outcomes, but also strongly associated with poor response to Doc-based chemotherapy. We also found that IDC-P status could be considered as a novel predictive marker in helping physicians precluding Doc as first-line therapy in IDC-P(+) patients. Also, these findings require large-scale prospective validation.
Single-dose, four-way crossover, open-label, relative bioavailability (BA) studies of a novel formulation of abiraterone acetate (AA) versus the reference formulation under fasted conditions in healthy male subjects.
Authors: Goldwater Ronald , Hussaini Azra , Zhang Yuxin , Bosch Bill , Nemeth Paul
Published: March 2017

e605

Background: AA is approved for treatment of metastatic castration-resistant prostate cancer. The originator AA (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure in healthy subjects. AA fine particle (AAFP) is a proprietary formulation (utilizing SoluMatrix Fine-Particle Technology) that was designed to provide improved BA versus the OAA formulation. Methods: In Study 1, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg. To further expand the AAFP dose range, 36 subjects were randomized in a crossover design to AAFP 125, 500, or 625 mg or OAA 1000 mg in Study 2. Both studies included a 7-day washout period prior to crossover. Results: AAFP 500 mg BA relative to OAA 1000 mg measured by the ratio of test-to-reference geometric means was AUC0-t 93.4% (90% CI: 85.3–102.4%), AUC0-∞ 91.0% (90% CI: 83.3–99.4%), and Cmax99.8% (90% CI: 86.3–115.5%). Dose proportionality was seen across all AAFP dose levels (see table). Between-subject variability for AAFP 500 and 625 mg was similar to OAA 1000 mg. No significant AAFP-related adverse events (AEs), serious AEs, or deaths occurred. Treatment-emergent AEs were mostly Grade 1. Conclusions: AAFP demonstrated improved BA and AAFP 500 mg was bioequivalent to OAA 1000 mg in healthy male volunteers under single dose and fasted conditions. AAFP showed dose proportionality across all doses studied (100–625 mg). Clinical trial information: NCT02737332. [Table: see text]
Avian torpor or alternative thermoregulatory strategies for overwintering?
Authors: Douglas Tegan K. , Cooper Christine E. , Withers Philip C.
Published: March 2017

It is unclear whether torpor really is uncommon amongst passerine birds. We therefore examined body temperature and thermoregulatory strategies of an Austral passerine, the white-browed babbler (Pomatostomus superciliosus), which has characteristics related to a high probability of torpor use; it is a sedentary, insectivorous, cooperative breeding species, which we studied during winter in a temperate habitat. Wild, free-living babblers maintained normothermy overnight, even at sub-zero ambient temperatures, with a mean minimum body temperature of 38.5±0.04°C that was independent of minimum black bulb temperature. Physiological variables measured in the laboratory revealed that babblers had a low basal metabolic rate and evaporative water loss, but their body temperature and thermal conductance were typical of those of other birds and they had a typical endothermic response to low ambient temperature. Huddling yielded significant energy savings at low temperatures and a roost nest created a microclimate that buffered against low temperatures. Low basal energy requirements, communal roosting and the insulation of a roost nest confer sufficient energetic benefits, allowing babblers to meet energy requirements without resorting to heterothermia, even in their depauperate, low-productivity landscape, suggesting that passerine birds use alternatives to torpor to balance their energy budgets when possible.
Loss of the RNA helicase SKIV2L2 impairs mitotic progression and replication-dependent histone mRNA turnover in murine cell lines
Authors: Onderak Alexis M. , Anderson James T.
Published: March 2017

RNA surveillance via the nuclear exosome requires cofactors such as the helicase SKIV2L2 to process and degrade certain noncoding RNAs. This research aimed to characterize the phenotype associated with RNAi knockdown of Skiv2l2 in two murine cancer cell lines: Neuro2A and P19. SKIV2L2 depletion in Neuro2A and P19 cells induced changes in gene expression indicative of cell differentiation and reduced cellular proliferation by 30%. Propidium iodide-based cell-cycle analysis of Skiv2l2 knockdown cells revealed defective progression through the G2/M phase and an accumulation of mitotic cells, suggesting SKIV2L2 contributes to mitotic progression. Since SKIV2L2 targets RNAs to the nuclear exosome for processing and degradation, we identified RNA targets elevated in cells depleted of SKIV2L2 that could account for the observed twofold increase in mitotic cells. Skiv2l2 knockdown cells accumulated replication-dependent histone mRNAs, among other RNAs, that could impede mitotic progression and indirectly trigger differentiation.
EVOLUTION OF AMERICAN OPTION VALUE FUNCTION ON A DIVIDEND PAYING STOCK UNDER JUMP-DIFFUSION PROCESSES
Authors: Рехман Назир , Rekhman Nazir , Хуссейн Закир , Khusseyn Zakir , Али Файха , Ali Faykha , Бендерская Ольга , Benderskaya Olga , Хуссейн Султан , Khusseyn Sultan , Зуев Сергей , Zuev Sergey
Published: March 2017

This work is devoted to the analysis and evolution of the value function of American type options on a dividend paying stock under jump diffusion processes. An equivalent form of the value function is obtained and analyzed. Moreover, variational inequalities satisfied by this function are investigated. These results can be used to investigate the optimal hedging strategies and optimal exercise boundaries of the corresponding options.
MICROSTRUCTURES, MECHANICAL PROPERTIES INGOT AlSi7Fe1 AFTER BLOWING OXYGEN THROUGH MELT
Authors: Finkelstein Arkady B. , Schaefer Arseny , Chikova Оlga А.
Published: March 2017

The new technology of producing ingot of AlSi7Fe1 high-strength is described. This new technology consists in saturation of melt with hydrogen, with further blowing with oxygen. Studied the microstructure, phase composition and mechanical properties of ingot after blowing oxygen of melt and ingot obtained with the traditional method. Have suggested that in liquid aluminum alloy AlSi7Fe1 because of blowing with oxygen arise refractory particles Al2O3. These particles Al2O3 further in crystallization serve as a modifier of the microstructure of ingot. Mostly observed modifications of eutectic phases. Thus saturation of melt with hydrogen, with further blowing with oxygen provides an increased tensile strength of ingot AlSi7Fe1.
NIOBIUM EFFECT ON BASE METAL AND HEAT AFFECTED ZONE MICROSTRUCTURE OF GIRTH WELDED JOINTS
Authors: Di Schino Andrea , Di Nunzio Paolo Emilio
Published: March 2017

The development of steels for line pipes during the last decades has been driven by the need to obtain improved combinations of high strength, toughness, weldability on industrial scale at affordable prices. The effect of niobium content on the heat affected zone (HAZ) microstructure is reported in this paper. Niobium, for its specific thermodynamic and kinetic attitude to form carbide and nitride precipitates, played a key role in the development of modern HSLA steels Results show that niobium addition is able to refine both the bainitic packet and cells size in the heat affected zone during welding. This implies that niobium addition leads to an improvement of both toughness and hardness of welded joints manufactured by Nb micro-alloyed steels.
Liquidity Provision and the Cross Section of Hedge Fund Returns
Authors: Jame Russell
Published: March 2017

I investigate whether hedge funds that supply liquidity earn superior returns. Using transaction data, I find that hedge funds following short-term contrarian strategies (i.e., liquidity suppliers) earn significantly higher returns on their equity trades and holdings. Similarly, using commercial databases, I find that hedge funds with greater exposure to a liquidity provision factor earn significantly higher excess returns and Sharpe ratios. The superior performance of liquidity-supplying hedge funds arises from strategies that are more complex than mechanical short-term reversal strategies. For example, among stocks with similar past returns, liquidity-supplying funds are more likely to trade against stocks heavily traded by constrained mutual funds and less likely to trade against stocks heavily traded by unconstrained mutual funds. The outperformance of liquidity-supplying funds is also concentrated in periods of low funding liquidity, suggesting that less-binding financial constraints contribute to their superior returns.

The Internet appendix is available at https://doi.org/10.1287/mnsc.2016.2687

This paper was accepted by Lauren Cohen, finance.
Convergence In Future Wireless Network Technology
Authors: Azeem Shaikh , Sharma Satyendra
Published: March 2017

The communications sector is undergoing significant changes, with the emergence of a number of platforms available to provide a different range of services. Some of these platforms are complementary to each other, while others are competitive, or can provide a valid substitute for some of the services provided. Up till now, the most important communications platform in most of the developing countries has been the public switched telecommunication network (PSTN) which provides access to all households and buildings. This universality in providing access has also meant that the network has generally been designated as one for universal service.
Improving E-Learning Support and Infrastructure in Different Districts of Jammu and Kashmir
Authors: Akram Wasim , Ahlawat Jagbir
Published: March 2017

This paper reports a study conducted in 2015 at the different institutions of different of Jammu and Kashmir aimed to obtain a much clearer picture about the use and knowledge of e-learning at the institutions so as to give new idea about development of e-learning (online courses) usage in institutions. Multiple sources of data were collected, including: questionnaires and interviews with academics, students and administration. The information illustrate that e-learning (online courses) in institutions of Jammu and Kashmir is still largely in the “innovators” and “early adopters” stages. There lies a “chasm” ahead inhibiting moving further into the “mainstream” area. The analysis of the information revealed that how much the academics and students know about the e-learning (online courses) and how much they are implementing in their lectures/studies. The focus of the chapter is on how one can strengthen this alignment to be able to bridge the chasm. The study has been successful in eliciting institutions support for changes to the e-learning support system.
Security Enhancement of AODV Protocol using Fuzzy based Trust Computation in Mobile Ad Hoc Networks
Authors: Jain Ashish , Tokekar Vrinda
Published: March 2017

Mobile ad hoc network (MANET) possess self-configuration, self-control and self-maintenance capabilities. Nodes of MANET are autonomous routers. Hence, they are vulnerable to security attacks. Collaborative attacks such as black hole and wormhole in MANET are difficult to be detected and prevented. Trust based routing decision is an effective approach for security enhancement in MANET. In this study, trust computing using fuzzy based max-product composition scheme is applied to compute aggregated trust values to determine malicious nodes and thereby safe route in MANETs. The results show performance improvement of proposed protocol over AODV protocol. Network metrics are analysed under different mobility conditions and different positions of black hole nodes.
Noise Removal and Filtering Techniques used in Medical Images
Authors: Kumar Nalin , Nachamai M
Published: March 2017

Noise removal techniques have become an essential practice in medical imaging application for the study of anatomical structure and image processing of MRI medical images. To report these issues many de-noising algorithm has been developed like Weiner filter, Gaussian filter, median filter etc. In this research work is done with only three of the above filters which are already mentioned were successfully used in medical imaging. The most commonly affected noises in medical MRI image are Salt and Pepper, Speckle, Gaussian and Poisson noise. The medical images taken for comparison include MRI images, in gray scale and RGB. The performances of these algorithms are examined for various noise types which are salt-and-pepper, Poisson, speckle, blurred and Gaussian Noise. The evaluation of these algorithms is done by the measures of the image file size, histogram and clarity scale of the images. The median filter performs better for removing salt-and-pepper noise and Poisson Noise for images in gray scale, and Weiner filter performs better for removing Speckle and Gaussian Noise and Gaussian filter for the Blurred Noise as suggested in the experimental results.
Phoneme Segmentation of Tamil Speech Signals Using Spectral Transition Measure
Authors: Geetha K , Vadivel R
Published: March 2017

Process of identifying the end points of the acoustic units of the speech signal is called speech segmentation. Speech recognition systems can be designed using sub-word unit like phoneme. A Phoneme is the smallest unit of the language. It is context dependent and tedious to find the boundary. Automated phoneme segmentation is carried in researches using Short term Energy, Convex hull, Formant, Spectral Transition Measure(STM), Group Delay Functions, Bayesian Information Criterion, etc. In this research work, STM is used to find the phoneme boundary of Tamil speech utterances. Tamil spoken word dataset was prepared with 30 words uttered by 4 native speakers with a high quality microphone. The performance of the segmentation is analysed and results are presented.
Fuzzy Logic based Stock Value Prediction using Fundamental Analysis
Authors: Mangale Chittaranjan , Meena Shyam , Purohit Preetesh
Published: March 2017

Stock market is very versatile and fluctuates with time. For the same way it becomes difficult to predict movement of the stock, there are various approaches and tools through which the price of the stock is determined by the past patterns. Mostly the approaches are in terms of fundamental approach and technical approach. For the long-term valuation fundamental approach is used. Every stock is having its own value that does not depend on the price of the stock that is known as Intrinsic value. The proposed model works through phases of data collection, feature processing, fuzzy logic mapping and stock value calculation. Fuzzy logic is used to map the quality as well as quantity valuation factors. The IF THEN rules are applied on the linguistic variable. The fuzzy model outcomes the stock value which is used to provide stock worth. The stock value is calculated by Dividend discount model. Accuracy of the system is 0.77. The results offer the backbone for the value and not the price.
Comparative evaluation of WOFOST and CERES-rice models in simulating yield of rice cultivars at Navari
Authors: Hadiya Nilesh , Kumar Neeraj , Mote B. M , Thumar Chiragkumar , Patil D.
Published: March 2017

A field experiment was conducted during kharif season of 2015 to assess the prediction performance of CERES-Rice and WOFOST model for grain and straw yield of three rice cultivars viz., (V1:Jaya, V2: Gurjari and V3: GNR-2) sown under four different environments viz., (D1: 10/07/2015, D2: 25/07/2015, D3: 09/08/2015 and D4: 24/08/2015) with two nitrogen levels N1:75 and N2:100 kg NPK/ha-1.Results showed that the prediction of WOFOST model forgrain yield of rice cultivars under different treatments more close to the corresponding observed value with percent error PE between (18.66%)as camper to CERES-rice model with PE (28.56%), but for straw yield CERES-rice model give more close prediction than WOFOST model with PE (20.99%) and (27.33%) between predicted and observed value.
A comparative finite element study of stress and deformation on three commonly used all ceramic fixed denture prosthesis under the influence of different bite forces
Authors: Raghavan Rohit , S Raj Jency , M Kunjappan Shiji , Christopher Kiran , Kambiranda Sapna C
Published: March 2017

Aim: To simplify the complexity in design, modeling and analysis of Fixed Partial Dentures (FPD) and to evaluate the maximum stress and deformation developed using Finite-Element Method.Materials and Methods: The specimen was created based on monoblock concept. The monoblock concept assumes that the total FPD unit, i.e., Abutment, pontic, connector and retainer together will act as a single unit. Monoblock castings do not differ from those made in segments and later welded as regard to the distribution of stresses. The Specimen of dimension 30 X 5 X 5mm were made of the three commonly used FPD materials such as feldspathic ceramics, Lithium di silicate and Zirconia. Rectangle shape was considered with notches at 1 X 450 as a close approximation of actual FPDs. The modeling was done using Solid Works 2012, and analysis was carried out using ANSYS Mechanical APDL R14.5. The maximum stress and deformations corresponding to various masticatory loads (100 N, 500 N, 600N, 800 N & 1000 N) were found out, and the results were compared with previous studies in FPD.Results: The results revealed that the maximum principal stress and deformation are found at the centre of the pontic. Furthermore, it was found that for all masticatory loads, the maximum stress and deformation were encountered in Feldspathic ceramic and least for Zirconia.Conclusion: A less complex model using the monoblock concept was developed to design and analyze FPD, so that the meshing complexities, computational time and cost can be reduced drastically. The results could well be considered as a benchmark in FPD-related studies.
Opinions of university students regarding pictorial warnings on cigarettes packs
Üniversite öğrencilerinin sigara paketleri üzerindeki resimli uyarılar hakkındaki görüşleri
Authors: Özpulat Funda , Bilir Nazmi
Published: March 2017

This descriptive study was conducted on totally 460 students from the departments of nutrition and dietetic (n=143) and nursing (n=317) of a health college located in Akşehir County of Konya City in the period of December 1st-31st, 2015. Within the scope of the study, age, gender, department and grade characteristics of students, their individual and family member’s status in terms of consuming tobacco products, and their opinions regarding pictorial warnings to be printed on cigarettes packs, regulated by the European Union published on 17.12.2014.As a result of the study, it was determined that students’ opinions regarding efficiency of written and pictorial warnings on cigarettes packs were differing with respect to students’ gender and sigarettes usage status; and that illustrations on cigarettes packs were found more effective by female students and non-cigarettes user.Especially activities such as training programs, seminars/congress/conferences for male students and cigarettes users about tobacco products and their harms could contribute in raising awareness of university youth. Additionally, placing impressive or even scary images in larger sizes emphasizing serious health problems on cigarettespacks could be effective on significant decrease of usage of tobacco products. ÖzetKonya İli Akşehir İlçesinde yer alan bir sağlık yüksekokulunun beslenme diyetetik (n=143) ve hemşirelik bölümünden (n=317) toplam 460 öğrencinin katılımıyla gerçekleştirilen tanımlayıcı tipteki bu çalışma 1-31 Aralık 2015 tarihleri arasında uygulanmıştır. Çalışma kapsamında, öğrencilerin yaşı, cinsiyeti, bölümü, sınıfı, kendisinin ve aile bireylerinin tütün ürünlerini kullanma durumu gibi bazı özellikleri ile sigara paketleri üzerine basılmak üzere Avrupa Birliği tarafından 17.12.2014 tarihinde yayınlanan resimli uyarılar hakkındaki düşünceleri öğrenilmiştir.Yapılan çalışma sonucunda, sigara paketleri üzerindeki yazılı ve görsel uyarıları etkili bulma durumunun öğrencilerin cinsiyetine ve sigara kullanma durumuna göre değiştiği, kız öğrencilerin ve sigara kullanmayanların sigara paketleri üzerindeki ifadeleri daha etkili buldukları saptanmıştır.Özellikle erkek öğrencilere ve sigara kullananlara tütün ürünleri ve zararlarına yönelik düzenlenecek eğitim programları, seminer/kongre/konferans türü etkinlikler üniversite gençliğinin farkındalık düzeyinin arttırılmasına ve bilinçlendirilmelerine katkıda bulunacaktır. Ayrıca, sigara paketleri üzerine daha geniş alanı kapsayan, daha ciddi sağlık sorunlarına işaret eden çarpıcı hatta ürkütücü resimlerin basılması tütün ürünlerinin kullanılmasının önemli ölçüde azaltılmasında etkili olabilir.
Konflik Penambangan Batugamping Kecamatan Ponjong dalam Tinjauan Arena Bourdieu
Authors: Reinhart Hilary
Published: March 2017

Limestone mining is a problem in the karst area because it causes environmental degradation, social change from the agrarian to industrial, and conflicts among stakeholders. Therefore, the limestone mining is not only identified as the environmental damage problems but also environmental management problems. The article aimed to explain an overview of the mining conflicts in the karst region. On the other hand, this study also provided a new approach in understanding the conflicts of mining. The study was conducted using qualitative descriptive analysis. Analyses were performed using stakeholder mapping and potential conflicts between stakeholders. The mapping results were contextualized using field and capital approach of Pierre Bourdieu theory. The approach used to understand the direction of conflicts and capital contestation of each author. The capital analysis showed that the government, namely the Energy and Mineral Resources in various levels of bureaucracy has the dominant capital in the arena of limestone mining in Ponjong District because it has a complete capital and outperforms of the other actors. It concludes that the differences types of capital affect the actors to take the position in an arena and each actor who has a robust capital sought to accumulate the capital to attain the main capital.