bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone (AP) for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on abiraterone.
Authors: Lin Jianqing , Sama Ashwin Reddy , Hoffman-Censits Jean H. , Kennedy Brooke , Kilpatrick Deborah , Ye Zhong , Yang Hushan , Mu Zhaomei , Leiby Benjamin E , Lewis Nancy , Cristofanilli Massimo , Kelly William Kevin 
Published: February 2017

311 Background: Aurora A kinase (AK) phosphorylates and interacts with androgen receptor (AR) and enhances AR DNA binding activity. We hypothesized that AK contributes to castration resistance in PCa, and targeting AK can inhibit AR function and re-sensitize PCa cells to AR signaling inhibitors such as abiraterone. Methods: Aphase I/II, open label, single institution trial to determine the safety and efficacy of AK inhibitor alisertib when given in combination with abiraterone plus prednisone (AP) was planned. Eligible subjects had mCRPC with disease progression on abiraterone. Androgen deprivation plus abiraterone and prednisone were maintained through the trial. Subjects were treated with dose escalation per standard 3+3 design. Planned 3 dose cohorts of alisertib were 30, 40, 50 mg PO BID D 1-7 every 21 D. Correlative studies included kinetics of neuroendocrine tumor markers, enumeration and AK gene amplification of CTCs. Results: Nine of 43 planned subjects were enrolled, 3 in cohort 1 without DLT. Two DLTs developed in cohort 2, thus 3 more patients were enrolled into cohort 1, and 2 developed DLT (total 2/6) in this cohort. The grade 3/4 toxicities (4/9) include neutropenic fever (1/9), neutropenia (1/9), fatigue with memory impairment (1/9), and mucositis (diarrhea and mouth sores, 1/9). Pharmacodynamically, adding alisertib did not affect circulating total testosterone and DHEA levels. Only one patient had decreased Chromogranin A level lasted for 4 months when compared to baseline. Four (4/9) patients had ≥ 5 CTCs at baseline but no conversion ( to < 5) was observed. No PSA decrease was observed during the study. Mean duration of study was 2.5 months. The toxicity / efficacy ratio did not warrant further dose expansion and the trial was terminated early after discussion with sponsor. Conclusions: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. Clinical trial information: NCT01848067.
The association of JAK2 polymorphisms with prognosis in castration-resistant prostate cancer (CRPC).
Authors: Zhang Ben Yiming , Riska Shaun M. , Mahoney Douglas W. , Cerhan James Robert , Costello Brian Addis , Dronca Roxana Stefania , Quevedo Fernando , Pitot Henry C. , Kohli Manish 
Published: February 2017

313 Background: We evaluated variation in candidate genes implicated in either initiation or progression of prostate cancer with survival in CRPC stage. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of > 5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model using Cox regression adjusted for age at CRCP and Gleason score (GS) were used. Results: Two hundred and forty five CRPC patients who met the criteria of having adequate DNA were genotyped (14 genes, 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS = 7 and 13% with GS < 7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level JAK2 was detected to be associated with OS. Six of 18 JAK2 SNPs were associated with OS after adjustment for age and GS as well as pruning of SNPs in high linkage disequilibrium with each other (see table). In our multivariate model including age, GS, rs2149556, and rs4372063, the adjusted HRs for rs2149556 and rs4372063 were 0.67 (95% CI 0.38-1.18) and 2.17 (95% CI 1.25-3.76), respectively. The protective effect of rs2149556 appears after adjusting for the presence of minor alleles for rs4372063 in this dataset. Conclusions: Germline variation in the JAK2gene is associated with survival in CRPC stage and warrants further validation as a potential prognostic biomarker. [Table: see text]
Urologists’ experiences with treatment of castration-resistant prostate cancer.
Authors: Geynisman Daniel M. , Doyle Jaime , Kutikov Alexander , Uzzo Robert G. , Wong Yu-Ning , Smaldone Marc C. 
Published: February 2017

315 Background: Urologists are at the forefront of treating prostate cancer. Since 2010 four non-chemotherapy drugs have been approved for castration-resistant prostate cancer (CRPC). We aimed to ascertain Society of Urologic Oncology (SUO) members’ practices, training, and barriers as they relate to the treatment of CRPC. Methods: An IRB approved nine item REDCap survey was emailed to 697 SUO members (440 US urologists) without a financial incentive. Urologists were asked whether they should and/or have treated men with CRPC, what barriers they experience and how these barriers may be overcome. Results: Eighty-four surveys were completed. 86% definitely or somewhat agreed that it was within the purview of urologists to prescribe therapy for CRPC. Abiraterone, enzalutamide, sipuleucel-T, or Radium-223 were prescribed by 51% and out of those, 44% personally prescribed them to > 50% of their CRPC patients; 52% were aware of other urologists who prescribed these drugs. Education on the use of these drugs was most commonly via self-study (19%), national meetings (19%), pharmaceutical representatives (17%), and informal discussions with colleagues (16%). Although some did not see barriers (27%), side-effects management (23%), the time it takes to counsel patients on these therapies (14%), and their practice’s time and energy costs (14%) were the greatest obstacles to using these medications. 34% felt that more educational sessions at national meetings or greater support by professional organizations would help them increase drug administration. 53% see the recent changes in the management of CRPC as increasing the collaboration between urologists and medical oncologists and 30% believe there are increasing opportunities for urologists to strengthen their relationship with their CRPC patients. Conclusions: The majority of SUO respondents agreed that it is within the scope and practice of urologists to prescribe therapy for CRPC. Half have prescribed these therapies themselves and/or were aware of other urologists who had done the same. Some would be encouraged to increase their use of therapies for CRPC via greater support by professional organizations and education at national meetings.
Identification of a predictive factor of metastatic castration-resistant prostate cancer patients’ response to alternative antiandrogen therapy with flutamide.
Authors: Yasui Masato , Yoneyama Shuko , Uemura Koichi , Kawahara Takashi , Hattori Yusuke , Teranishi Jun-ichi , Ohta Jun-ichi , Yokomizo Yumiko , Yao Masahiro , Taguri Masataka , Uemura Hiroji , Miyoshi Yasuhide 
Published: February 2017

321 Background: Recently, new androgen pathway inhibitors, abiraterone and enzalutamide, are demonstrated to improve overall survival for metastatic castration-resistant prostate cancer (mCRPC). In Japan, alternative antiandrogen (AA) as second-line hormonal therapy for mCRPC that relapses after initial hormone therapy have been commonly used before new androgen pathway inhibitors. In this study, we attempted to identify the predictive factors for efficacy of AA as second-line hormone therapy. Methods: We identified consecutive 65 mCRPC patients treated with AA as second-line hormonal therapy. All patients were treated with maximum androgen blockade (MAB) initially and evaluated antiandrogen withdrawal syndrome after relapse. We analyzed the correlations between progression-free survival (PFS) of AA and clinicopathological characteristics, including patients’ age, initial PSA levels, PSA levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease (EOD) classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB. Results: The median duration of prostate cancer sensitivity to MAB was 11.3 months (range: 1.5-53.0 months). In multivariate analysis, four significant risk factors for poor PFS were identified; initial PSA levels ( > 263 ng/mL vs ≤ 263; HR 0.53, p = 0.038), N stage (1 vs 0; HR 3.00, p = 0.001), EOD classifications (3-4 vs 1-2; HR 2.50, p = 0.007), and the previous duration of prostate cancer sensitivity to MAB ( < 12 months vs ≥ 12; HR 2.16, p = 0.026). We stratified the patients into two cohorts with low risk (0-2 risk factor present) and high risk (3-4 risk factors present). We found a significant difference in PFS among risk groups (median PFS 7.3 months vs 1.5, p < 0.000). Conclusions: Initial PSA, N stage, EOD classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB were the significant predictive factors for efficacy of AA as second-line hormone therapy in patients with mCRPC. These findings might support that decision-making of when to start the new AR pathway inhibitors.
Is metronomic cyclophosphamide (mCTX) a therapeutic option for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) in the era of new agents (NAs)? A retrospective multicenter Italian study.
Authors: Caffo Orazio , De Giorgi Ugo , Ferraú Francesco , Donini Maddalena , Facchini Gaetano , Maruzzo Marco , Tucci Marcello , Conteduca Vincenza , Maines Francesca , Rossi Lorena , Veccia Antonello , Galligioni Enzo 
Published: February 2017

326 Background: Several NAs, such as abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ), are able to significantly prolong mCRPC pts survival after docetaxel (DOC) failure. Nevertheless, all pts eventually show progressive disease with NAs and several pts may require further treatment. mCTX was considered as a feasible and tolerable therapeutic option after DOC failure before the introduction of NAs in the clinical practice. The present retrospective study describes the clinical outcomes of mCTX, used in mCRPC pts after the failure of both DOC and at least one NA. Methods: We retrospectively reviewed the clinical records of all mCRPC pts treated in 8 Italian hospitals after the introduction of NAs in the clinical practice. We considered as eligible for the present analysis all pts who received mCTX after DOC and at least one NA. All pts were treated with CTX 50 mg po daily until disease progression. Results: From December 2011 to June 2015, a consecutive series of 48 mCRPC pts, median age 72 yrs (56-90), with bone (94%), nodal (67%) or visceral (25%) mets, was treated with mCTX. All pts have previously received a DOC-based chemotherapy followed by only one NA in 21 cases, two NAs in 20, and all three NAs in 7. The median duration of the treatment was 10.4 wks (range 3.6-61.1). Recorded grade 3-4 toxicities were: anemia (5 pts), leucopenia (1), thrombocytopenia (2), fatigue (2), and anorexia (1). Seven pts (14%) achieved a PSA reduction ≥ 50% and 2 (4%) an objective response. The median progression free survival (PFS) was 3.5 mos with 7 pts (14%) showing a PFS ≥ 9 mos. The median overall survival was 6.9 mos. Conclusions: In our experience, mCTX was a feasible and well tolerated therapeutic option in heavily pre-treated pts with very advanced mCRPC. Despite its activity was limited, the clinical outcomes of this cheap treatment are similar to those observed with NAs administered in third/fourth line with a quote of pts experiencing a prolonged disease control. Prospective studies are needed to define the therapeutic role of mCTX after NAs in mCRPC pts.
Prospective evaluation of the response to prednisone-dexamethasone switch in castration-resistant prostate cancer patients treated with abiraterone pre- and post-docetaxel.
Authors: Romero-Laorden Nuria , Castro Elena , Lozano Rebeca , Sáez M Isabel , Valero Jeannette , Van de Poll Floortje , Nombela M Paz , Rodriguez-Moreno Juan Francisco , Montesa A. , Grau Gala , Rivera Leticia , Olmos David 
Published: February 2017

327 Background: Abiraterone acetate (AA) administered with prednisone (P) to reduce mineralocorticoid-related adverse events improves survival in CRPC with a favourable tolerance profile. However, in the phase I/II of AA without steroids, dexamethasone 0,5mg/day was added after biochemical progression reaching a 25% of PSA decline. Lorente et al (BJC, 2014) showed durable biochemical responses in 40% of cases treated with AA and steroid switch in the post-docetaxel setting. We hypothesize that P to D switch in patients with biochemical progression to AA+P would lead to secondary responses also in the pre-docetaxel setting. Methods: Change of P 5mg/12h to D 0.5mg/24h was prospectively tested in clinically stable CRPC with biochemical progression ( > 25% PSA rise over nadir, confirmed in a second determination) and/or limited radiological progression ( < 3 new bone/lymphatic metastasis, non-bulky), after ³12 weeks of AA+P. PSA was monitored q4wks. CT- & bone-scans were performed every 12-16 weeks. Biochemical and radiological responses were evaluated by PSAWG2 and RECIST criteria. Survival outcomes were calculated using Kaplan-Meier method. Results: 18 patients were included (11 pre- & 7 post-docetaxel). Median age 72 (60-85); visceral, bone and/or lymph metastasis were present in 17%, 83% and 50% of patients. Median PSA at AA+P and AA+D commencement was 81 ng/ml and 100ng/ml, respectively. Biochemical response was observed in 83% of patients: 56% with a PSA decrease ≥ 30%, and 28% with PSA decrease ≥ 50%. Median biochemical progression-free survival (bPFS) with AA+P was 5.7 months (CI95% 2.9-9.1) and 3.8m (CI95% 1.4-6.5) in the pre- and post-docetaxel setting, respectively. Median bPFS with AA+D was 5.4m (1.2-8.8) and 2.5 (CI95% 1.1-2.9) in the pre- and post-docetaxel settings. Two radiological partial responses were observed with AA+D. Conclusions: Clinically stable patients with limited disease progression after AA+P may benefit from steroid switch in both the pre- and post-docetaxel settings.
Characteristics of Chinese patients with advanced prostate cancer: A muliticentre, non-interventional, observational, prospective, registry study of docetaxel.
Authors: He Dalin , Sun Zhongquan , Guo Jianming , Zhang Zhigen , Shan Yuxi , Ma Lulin , Li Hanzhong , Jin Jie , Huang Yiran , Xiao Jiaquan , Wei Qiang , Ye Dingwei 
Published: February 2017

328 Background: Prostate cancer (PC) is the second most frequently diagnosed malignancy in males worldwide, and stands in 7th place among malignancies in Chinese males. This study investigated the real-world treatment patterns of docetaxel as chemotherapy in patients with advanced PC in China. Methods: This was a multi-center, prospective, observational, non-interventional, product registry study. All patients with advanced PC who failed with previous endocrine therapies, were receiving docetaxel containing chemotherapy, and consented to participate in the study were eligible to be enrolled. Patients were followed-up 2 years, for the collection and analysis of data on docetaxel treatment mode, prostate specific antigen (PSA) remission rate, survival time, etc. Results: A total of 407 patients were enrolled from Aug 2011 through Jun 2014, with a mean Gleason score of 8.0 (SD: 1.11), and median PSA of 61.0 (range: 0.0 to 5000.0) ng/ml. 302 (74.2%) patients were classified as clinical stage IV. For Eastern Cooperative Oncology Group (ECOG) score, 145 (35.6%), 205 (50.4%), 48 (11.8%), patients had scores of 0, 1, 2, respectively. Metastasis to bone was present in 340 (83.5%) patients; metastasis to other organs (liver, lungs, adrenal glands, brain, etc.) was present in 57 (14.0%) patients. Last disease progression prior to enrolment was evidenced by tumor progression in 132 (32.4%) patients and by PSA elevation in 379 (93.1%) patients. 173 (43.0%) and 120 (29.9%) patients started docetaxel therapy after failure of the first line and second line endocrine therapies, respectively; 51 (12.7%) patients after failure of the third line or more endocrine therapies. Conclusions: This abstract presented characteristics of Chinese patients with advanced PC revealed by a Chinese PC study, which indicated Chinese patients were in later stage and higher risk compared with their western counterparts. The majority of patients started docetaxel therapy after failure of first line and second line endocrine therapies. PSA elevation and tumor progression were the 2 main causes that Urologists determined for disease progression. Clinical trial information: no registration number.
Analytical challenges in quantitative analysis (LC/MS/MS) of abiraterone: A validated assay to determine abiraterone in human plasma.
Authors: Benoist Mette , van der Meulen Eric , Van Oort Inge , Gerritsen Winald , Schalken Jack , Burger David , van Erp Nielka P 
Published: February 2017

329 Background: Abiraterone acetate is rapidly hydrolyzed to the active abiraterone in vivo. In order to study the relation between drug exposure and therapeutic effect an assay to determine plasma concentrations of abiraterone is required. A quantitative bioanalytical liquid chromatography tandem mass spectrometric (LC-MS/MS) assay with a BEH C18(2.1 × 50 mm, 1.7 µm) column was developed. Several analytical challenges were encountered. Methods: Protein precipitation with acetonitrile was used to pretreat the EDTA plasma samples. A stable isotope (D4-abiraterone) was used as the internal standard. During validation five quality controls were used (LLOQ, LQ, MQ, HQ, ULOQ). The method was validated according to EMA guidelines. Results: The LC-MS/MS method was validated over a concentration range from 1-500 ng/mL. Within – and between day precisions and accuracies were < 5%. The LLOQ was 1 ng/ml and the ULOQ was 499 ng/mL. Abiraterone is stable in plasma for at least 7 days at ambient temperature and at 2-8°C. Stability at -40°C was demonstrated for at least 6 months. Abiraterone is only stable for 3 hours in whole blood at ambient temperature. Stock solution stability was demonstrated for at least 1 year. The concentration levels of the LQ, MQ and HQ were 5, 300 and 400 ng/mL, respectively. During method development several analytical challenges were encountered and solved: abiraterone adsorption on glass containers, limited stability in citrate plasma and whole blood, carry-over issues, very limited stability of abiraterone acetate in whole blood was demonstrated, curiously with proven stability in plasma. Throughout the method polypropylene vials and utilities were used. EDTA plasma was used for development and validation. The needle wash was adjusted and the runtime was prolonged with a longer time at 100% acetonitrile to address the carry over issues. Whole blood samples were treated on ice. The quantification of abiraterone acetate was abandoned. Conclusions: After different hurdles the method is successfully validated and applied to determine plasma concentrations of abiraterone in clinical studies and in regular patient care in patients with prostate cancer.
Development and validation of a bioanalytical assay on LC/MS/MS to quantify enzalutamide and N-desmethylenzalutamide in human plasma.
Authors: Benoist Mette , van der Meulen Eric , Van Oort Inge , Schalken Jack , Gerritsen Winald , Burger David , van Erp Nielka P 
Published: February 2017

330 Background: To study the relation between drug exposure and therapeutic effect of enzalutamide and its equipotent metabolite N-desmethylenzalutamide, a bioanalytical assay on liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated to determine plasma concentrations in vivo. Methods: Plasma samples were diluted 10-fold with 20% albumin solution. Protein precipitation with acetonitrile was used to pretreat the diluted plasma. A stable isotope (D6-enzalutamide) was used as the internal standard. During validation five quality controls were used (LLOQ, LQ, MQ, HQ, ULOQ). The method was validated according to EMA guidelines. Results: The LC-MS/MS method was validated over a concentration range from 500-50,000 ng/mL. Within – and between day precisions and accuracies were < 5.1%. The LLOQ of the method was set at 500 ng/ml and the ULOQ was 50,000 ng/mL. Enzalutamide and N-desmethylenzalutamide are stable in plasma for at least 19 days at ambient temperature and at 2-8°C. Stability at -40°C was demonstrated for at least 3 months. Enzalutamide and N-desmethylenzalutamide are stable for at least for 24 hours in whole blood at ambient temperature. Stock solution stability was demonstrated for at least 5 months. Concentration levels of the LQ, MQ and HQ were 1000, 15,015 and 40,040 ng/mL. Conclusions: The bioanalytical method to quantify enzalutamide and N-desmethylenzalutamide is successfully developed and validated. The bioanalytical method is used to support pharmacokinetic study questions and for regular patient care in patients with prostate cancer.
A live cell microfluidics device utilizing phenotypic biomarkers for prostate cancer.
Authors: Albala David , Mouraviev Vladimir , Rieger-Christ Kimberly M. , Sullivan Travis B. , Kella Naveen , Knopf Kevin B. , Rashid Hani H. , Manak Michael S. , Hogan Brad J. , Dixit Gauri , Berger Delaney , Su Wendell R. , Whitfield Matthew J. , Varsanik Jonathan S. , Foroohar Mani , Zappala Stephen M , Chander Ashok C. , Sant Grannum R. 
Published: February 2017

338 Background: A novel tissue based biomarker panel is introduced to objectively assess disease aggressiveness and invasive potential of Prostate Cancer (CaP). The biomarker diagnostic platform incorporates both molecular and phenotypic data that may allow an improved understanding of local growth and metastatic potential. The tissue based diagnostic incorporates matrix biology, phenotypic biomarkers, microfluidics, and machine vision. This technology presents the opportunity to culture samples, and both determine and automate biomarker measurements from machine vision algorithm analysis. Data are presented towards clinical validation, the ability to risk stratify, and prediction of local aggressiveness and metastasis. Methods: Conditions were optimized for reliably culturing primary cancer cells in vitro by simulating in vivo conditions on an extracellular matrix formulation. A mcirofluidics device was used to culture live tumor samples ex vivo enabling automated imaging of the label free and label-based biomarkers. Results: The validation study was IRB approved and performed in 200 consecutive CaP radical prostatectomy derived specimens collected between 03/2014 and 09/2015. Data was analyzed with receiver operating characteristics (ROC) generated Area-under-the-Curve (AUC) and specifically included capsular penetration, seminal vesicle invasion, as well as margin-positive disease. AUC Graphs are presented. The study further demonstrated that a normal set of phenotypic biomarkers can produce secondary metrics termed oncogenic potential (OP) and metastatic potential (MP). Concordance analysis supports that OP and MP are integral for distinguishing between benign histology and malignancy, predicting both stage and adverse pathology such as extra-prostatic extension (EPE) and lympho-vascular invasion (LVI). The study results demonstrate AUCs greater than 0.90 in predicting EPE and LVI. Conclusions: Results support the clinical validation of a novel live- cell phenotypic in vitro tumor diagnostic test. This test has the potential to predict adverse pathologies for CaP and may have extended clinical applications to optimize staging and risk stratification.