bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) pts receiving a new agent (NA)-based third line treatment: Preliminary results from a multicenter Italian study.
Authors: Caffo Orazio , De Giorgi Ugo , Alesini Daniele , Fratino Lucia , Ortega Cinzia , Tucci Marcello , Scagliarini Sarah , Zagonel Vittorina , Zucali Paolo Andrea , Morelli Franco , Sartori Donata , Sabbatini Roberto , D'Angelo Alessandro , Donini Maddalena , Barni Sandro , Procopio Giuseppe , Sirotova Zuzana , Sava Teodoro , Conteduca Vincenza , Galligioni Enzo 
Published: February 2017

211 Background: The NLR is a marker of systemic inflammatory response: several studies investigated its prognostic relevance in mCRPC but to date no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcome and NLR in a large series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 291 mCRPC pts with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received a NA-based third line: 90 received AA, 123 CABA and 78 ENZ. At the time of this analysis, data on NLR were available for 198 pts (68%): AA 68 (75%) – CABA 80 (65%) – ENZ 50 (64%): the median value was 3.1 (IQR 2.2-4.7). In the univariate analyses, the NLR as a discrete variable using the median value of 3.1 as threshold, was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001 and p = 0.001, respectively). No association was observed with either biochemical or objective response. These results were confirmed at the multivariate analysis. In Kaplan-Meier analysis, the median OS from the start of third-line was higher (18.2 vs 8.1 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 6.3 and 3.5 in pts with NLR ≤ 3.1 and > 3.1, respectively. Conclusions: At the best of our knowledge, this is the first report on the NLR value in mCRPC third line treatment. From our preliminary data, it appears that NLR may be a prognostic and predictive factor in mCRPC pts, treated with NA-based third line.
Clinical and immunologic impact of short course enzalutamide without androgen deprivation therapy for biochemically recurrent prostate cancer.
Authors: Madan Ravi Amrit , Donahue Renee Nicole , Singh Harpreet , Karzai Fatima , Theoret Marc Robert , Heery Christopher Ryan , Strauss Julius , Harold Nancy , Couvillon Anna , Marte Jennifer L. , Hankin Amy , Grenga Italia , Chun Guinevere , Rosner Inger L. , McLeod David G. , Cordes Lisa M , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L. 
Published: February 2017

214 Background: Enzalutamide (enz) is FDA approved for advanced prostate cancer, but studies are evaluating enz in earlier stages of disease. We have conducted a clinical trial (NCT01875250) of enz ± a therapeutic vaccine in biochemically recurrent prostate cancer. Methods: Eligible patients (pts) had a PSA between 2.0-20.0 ng/ml, no metastatic disease and normal testosterone (T). Treatment for all pts included enz 160 mg daily for 84 days (D), but no T lowering therapy was permitted. This analysis evaluated all pts for the impact of enz on PSA and T regardless of randomization. Pts treated with Enz alone were evaluated for immune responses.The impact of the vaccine will be evaluated after protocol-defined requisite follow-up. Results: Median age for all pts (n = 34) was 66 years (range: 52-87), with a median on-study baseline PSA of 4.55 ng/ml (2.02-19.43). Common adverse events included fatigue and breast tenderness, but no pts discontinued enz for toxicity. The median PSA decline was 99% (range: 52% to > 99%) with 11/34 pts having undetectable nadirs. Median time to first PSA rise after 84 D course of enz was 29 D (13-70) and median recovery to baseline PSA in 25 evaluable pts was 190 D (84-469). T increased above normal limits in 18/34 pts (median Tmax = 802 ng/dl). Immune analysis (n = 12) indicated enz alone increased naïve T-cells and NK cells, and decreased several subsets of myeloid derived suppressor cells with a highly suppressive phenotype. Conclusions: The preliminary findings from this study suggest that short-course enz is well tolerated, leads to prolonged PSA suppression and enhanced immune responses in patients with biochemically recurrent prostate cancer. These immune studies provide the rationale for the use of enz in combination with immunotherapeutics in this and other malignancies. Clinical trial information: NCT01875250.
SOCS3 immunohistochemical expression to support the 2005 International Society of Urological Pathology (ISUP) modified Gleason grading system.
Authors: Petrone Gian Luigi , Pierconti Francesco , Martini Maurizio , Cenci Tonia , Larocca Luigi Maria 
Published: February 2017

216 Background: In the 2005 International Society of Urological Pathology (ISUP) Consensus Conference, a modified Gleason grading system for prostate cancer was proposed. (Epstein JI et al. Am J Surg Pathol 2005; 29:1228-1242) Afterwards an interobserver study among experts in genitourinary pathology proposed some modifications and refinements to the 2005 ISUP modified grading system concerning the cribriform pattern carcinoma that it should never be diagnosed as Gleason pattern 3, assigning Gleason pattern 4 to cribriform glands (Latour M et al. Am J Surg Pathol 2008; 32: 1532-1539; Epstein J I Journal of Urology 2010: 183:433-440). Methods: The study population consisted of 80 patients undergoing biopsies at the Institute of Urology of our hospital, between February 2012 and January 2013 stratified into 3 different categories on the basis of histologic pattern: 1) 20 patients with classical and modified Gleason score 3+3 = 6; 2) 30 patients with classical Gleason score 3+3 = 6 upgraded to Gleason score 7 according to the ISUP modified grading system; and 3) 30 patients with classical and modified Gleason score 3+4 = 7. We evaluate the immunohistochemical protein expression of the suppressor of cytokine signaling (SOCS) proteins 3 (SOCS3) in these three different group of prostatic cancer biopsies. Results: We found that the SOCS3 pattern staining negative (-) or with SOCS3 negative staining with weak intensity staining in less than 50% of neoplastic glands (+/-) increases progressively in concomitance with the rise of Gleason score and SOCS3 positivity (+), correlates with classical or modified Gleason score 6 (P = 0,0004 Fisher’s exact tests) and with classical Gleason score 3+3 = 6 upgraded to Gleason score 7 (P = 0,0010 Fisher’s exact tests). Conclusions: In conclusion our data seem to support from a molecular point of view the modified criteria by 2005 International Society of Urological Pathology (ISUP) Consensus Conference as well as the hypothesis that the diagnosis of Gleason cribriform pattern 3 virtually does not exist and cribriform glands-regardless of their size-are nearly always considered pattern 4.
Randomized phase II trial of docetaxel plus prednisolone with or without androgen deprivation treatment in castration-resistant prostate cancer.
Authors: Jeong Jae Ho , Hyun Hyejung , Jeong In Gab , Hong Jun Hyuk , Ahn Hanjong , Lee Jae-Lyun 
Published: February 2017

217 Background: Androgen deprivation therapy (ADT) has been the main treatment option for patients with locally advanced or metastatic prostate carcinoma. However, the impact of continued ADT on clinical outcomes in castration-resistant prostate cancer (CRPC) patients treated with cytotoxic chemotherapy is controversial. We conducted a randomized phase II study to assess the impact of continued ADT in patients with CRPC receiving docetaxel plus prednisolone chemotherapy. Methods: Patients with CRPC were randomly assigned (in a 1:1 ratio) to receive docetaxel (75mg/m2 every 3 weeks) plus prednisolone (5mg twice daily on days 1-21) with ADT (leuprolide 11.25 mg long-acting depo every 12 weeks, ADT group) and docetaxel plus prednisolone without ADT (No-ADT group). For patients in the No-ADT group, ADT was resumed at the end of chemotherapy. The primary endpoint was time to PSA progression. Secondary objectives included PSA response rates, progression-free survival (PFS), and overall survival (OS). Suspension of leuprolide support prevented the attainment of our original goal of enrolling 80 men. Results: Between April 2011 and July 2014, 45 patients were enrolled in this study; 23 patients were randomly assigned to the ADT group and 22 to the No-ADT group. The median age was 68 years (range = 49-81) and median baseline serum PSA was 60.3 ng/mL (interquartile range = 14.7-157.3). Time to PSA progression was 6.5 months in ADT group and 4.3 months in No-ADT group, respectively (P = 0.673). PSA response rates were 55.2% and 44.8% in the ADT group and the No-ADT group, respectively (P = 0.463). The median PFS and OS were 5.3 months and 19.4 months for ADT patients and 4.3 months and 20.8 months for No-ADT patients, respectively (P = 0.608, P = 0.635). The testosterone level rose to more than the castrate level in 5 (22.7%) patients of the No-ADT group. Conclusions: Clinical outcomes were not signiﬁcantly different when patients with CRPC received concurrent ADT, or were not so treated, when receiving docetaxel plus prednisolone chemotherapy. Clinical trial information: NCT01487902 Clinical trial information: NCT01487902.
ODM-204, a novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer.
Authors: Kallio Pekka , Oksala Riikka , Moilanen Anu , Riikonen Reetta , Rummakko Petteri , Malmström Chira , Mustonen Mika VJ 
Published: February 2017

230 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue androgens. Inhibiting AR and androgen biosynthesis together may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and AR. In vivo, ODM-204 shows favourable pharmacokinetic/ pharmacodynamics (PK/PD) properties in intact mature male monkeys and strong antitumor activity in VCaP xenograft. Methods: The inhibition of CYP17A1 by ODM-204 was studied by using human testicular microsomes and adrenal cortex cell line. Potency to human AR was demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. PK/PD relationships were evaluated in intact male mature monkeys after single and multiple doses of ODM-204 (10-30 mg/kg/day) by measuring plasma PK after several time points and serum testosterone (T), dehydroepiandrosterone (DHEA), luteinizing hormone (LH), aldosterone, and cortisol 5 hours after the daily dose. Efficacy was further studied in VCaP xenograft in intact male nude mice treated with ODM-204, enzalutamide (enza), abiraterone (abi), or enza+abi-combination for 28 days. Results: ODM-204 binds to AR with a high affinity (Ki47 nM) and selectivity, and has a high potency towards CYP17A1 (IC5022 nM). In intact monkeys, ODM-204 was well tolerated and showed good oral bioavailability with linear and dose proportional pharmacokinetics. Already after a single oral dose of ODM-204, serum T and DHEA were markedly suppressed. After multiple days of dosing, LH was increased, however, changes in cortisol and aldosterone were only minimal. In VCaP xenograft model, ODM-204 showed significant antitumor activity, better than single agent enza or abi, or their combination. Conclusions: ODM-204 is a novel, dual CYP17A1 and AR inhibitor for the treatment of CRPC. A clinical phase 1/2 dose-escalation trial (NCT02344017) is ongoing in patients with mCRPC to determine PK, PD, safety and anti-tumor activity of ODM-204.
Observation of CNS events in real-world use of enzalutamide (ENZ) and bicalutamide (BIC).
Authors: Behl Ajay , Ellis Lorie , Pilon Dominic , Lefebvre Patrick , Dawson Nancy Ann 
Published: February 2017

235 Background: TERRAIN, a randomized, double-blind, multi-center, phase II trial compared efficacy and safety of ENZ to BIC in men with mCRPC. Although ENZ and BIC fall within the same drug classification, rates of seizure and other central nervous system (CNS) events, observed in non-clinical trial populations have not been explored. The objective of this study was to compare rates of real world CNS events in patients treated with ENZ or BIC. Methods: Retrospective claims from Truven Health MarketScan database were used to identify patients with a PC diagnosis; ≥1 claim for ENZ or BIC (index date) after 9/1/2012; > 6 months of continuous eligibility prior to index date (baseline period) and no use of ENZ or BIC prior to index. Patients were followed until 12/2014 or loss to follow-up. Patients were excluded if they had a CNS condition or another cancer diagnosis during the baseline period. CNS conditions were defined as a diagnosis for amnesia or memory impairment, anxiety, ataxia, cognitive disorders, confusion, convulsions, disturbance in attention, dizziness, falls, fatigue/asthenia, hallucinations, headaches, insomnia, pain, paresthesia, seizures, weakness, or other CNS disorders. Kaplan-Meier (KM) survival curves were used to compare the KM rates of developing any CNS conditions between patients who initiated ENZ relative to patients who initiated BIC. A subgroup analysis of patients with metastatic disease was performed. Results: The table below compares the development of CNS conditions between ENZ and BIC patients. Conclusions: This study shows that rates of CNS events are significantly higher in patients initiating ENZ as compared to BIC, even when controlling for metastatic status. [Table: see text]
Effect of local therapy on the systemic anti-tumor response in prostate cancer.
Authors: Ross Ashley , Benzon Benjamin , Glavaris Stephanie , Simons Brian , Hughes Robert , Mullane Patrick , Miller Rebecca , Nugent Katriana , Shinder Brian , Blosser Richard , Tran Phuoc T. , Hurley Paula , Vuica-Ross Milena , Schaeffer Edward M. , Drake Charles G. 
Published: February 2017

243 Background: The genomic complexities and adaptability of aggressive cancer implies that it may only be eradicated by equally adaptable systems. Immune checkpoint blockade (such as that targeting PD−1 or CTLA−4) has shown dramatic and durable efficacy in immunogenic malignancies, but little or no benefit in less immunogenic cancers such as prostate cancer. Here we use a mouse model of prostate cancer to investigate whether local therapy can mount or augment an immune response to distant tumors. Methods: Immuno−competent FVB mice were bilaterally implanted with Myc−CAP cells to form isogenic grafts. Two weeks after tumor introduction, ablative therapies including radiation (stereotactically as a single 10 Gy fraction), cryoablation (two freeze−thaw cycles of less than −40 degree Celsius), whole tumor cauterization, or excision were applied to the larger graft in the presence of checkpoint blockade (intra−peritoneal anti−CTLA−4 or anti−PD1) or control injection (hamster anti−mouse IgG). Tumor sizes and mouse survival was recorded as was lymphocytic infiltrates which were characterized histologically and by flow cytometry. Results: Ablative therapies of cautery or cryoablation, but not excision or radiation caused a statistically significant delay in the growth of distant untreated tumors (P < 0.05 for both). Flow cytometric analysis demonstrated concurrent increases in the CD8+IFNgamma+ T cell population in the lymph nodes draining the untreated distant tumor. Flow also demonstrated an increase in CD4+FoxP3+ cells (P < 0.05 for each). Low dose anti−CTLA−4 therapy (1mg/kg) synergized with all local therapies to greatly increase survival and delay distant untreated tumor growth. This corresponded to an increase in activated T cells within distant tumors. Anti−PD−1 therapy did not synergize with local therapies. Conclusions: Some ablative local therapies (cautery, cryoablation) alone may incite an immune response in distant tumors. Checkpoint inhibition with low dose CTLA−4 blockade synergizes with all local therapies to incite a systemic anti−tumor response. PD−1 blockade has minimal effectiveness when combined with local therapies and may require combinatorial drug use for effectiveness in prostate cancer.
Characterization of plasma-derived and urinary exosomal microRNA from metastatic CRPC patients.
Authors: Ledet Elisa M. , Miller Patrick J. , Gambhira Ratish , Dotiwala Aryeneesh , Sartor A. Oliver 
Published: February 2017

248 Background: Exosomes are nano-sized (50-100nm) vesicles derived from normal and tumor cells that function in cell-cell communication. These vesicles and their nucleic acid cargo may potentially serve as biomarkers for assessment of risk stratification and therapeutic response. The goal of this study was to characterize exosome derived microRNA (miRNA) isolated from plasma (pExos) and urine (uExos) of metastatic CRPC patients. Methods: Plasma samples were obtained from 18 mCRPC patients and 1 normal control. Following exosome isolation, RNA extraction and library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data processing including alignment, duplicate removal, normalization, and variant calling. Visualization and differential analyses were performed with SNP & Variation Suite v8.x. RNA derived from uExos was amplified using whole transcriptome amplification and interrogated with Prostate Cancer (PCa) miScript miRNA PCR Array. Results: Exosomes from both plasma and urine had similar amounts of miRNA/total RNA with average 34% miRNA (range 19%-51%). pExos had larger RNA fragments (range 10-333 nt) while uExos were more highly fragmented (range 10-60 nt). The amount of miRNA and fragmentation pattern was highly variable amongst patients. In pExos, RNA from PDPK1, USP9X, MAGI2, HMGA2 and PTGFR were present and previously shown in PCa. Also in pExos, miR941-2, miR4454, miR1302-2, miR143HG and miR22HG were annotated in prostate cancer patients; these miRNA have previously been identified in cancer. In uExos miR-16-5p and miR-375 were present and are shown to be differentially regulated in prostate cancer. Expression analyses will be presented. PCR validation is ongoing. Conclusions: The identification of cancer associated miRNA in pExos and uExos may potentially serve as biomarkers in mCRPC patients. The abundance and stability of miRNA contained in exosomes may provide insight into tumor evolution and disease progression. Additional studies evaluating the clinical relevance and prognostic value of exosomal miRNA are warranted.
Genomic characterization of primary and metastatic prostate cancer (PC) using a targeted next-generation sequencing assay.
Authors: Abida Wassim , Brennan Ryan , Armenia Joshua , Curtis Kristen Rebecca , Gopalan Anuradha , Arcila Maria E. , Danila Daniel Costin , Rathkopf Dana E. , Morris Michael J. , Slovin Susan F. , Solit David B. , Hyman David Michael , Durack Jeremy C. , Solomon Stephen Barnett , Reuter Victor E. , Taylor Barry S. , Berger Michael F. , Schultz Nikolaus , Scher Howard I. 
Published: February 2017

254 Background: Genomic alterations in PC have been described across the disease continuum, creating opportunities for selective clinical trial enrollment of patients (pts) with high-risk or metastatic disease based on their tumor profile. MSK-IMPACT is an exon capture-based sequencing assay performed in a CLIA-certified laboratory that targets 410 cancer-associated genes, many of which are potential drug targets. We assessed mutations and copy number alterations (CNAs) in primary and metastatic samples from untreated, hormone-treated and castration resistant pts. Methods: PC pts were enrolled on an IRB-approved protocol for tumor genomic profiling. Fixed tumor and matched germline samples were subjected to DNA sequencing analysis using MSK-IMPACT for the identification of somatic mutations and CNAs. Results: 315 samples from 271 pts were successfully sequenced (Table). Overall success rate was 80% (67% for bone). 14 tumors were pathologically classified as neuroendocrine or had neuroendocrine features. 23% of patients had tumor somatic alterations in DNA repair genes (BRCA2, BRCA1, ATM, FANCA and CDK12). Additional alterations were observed in PI3K, MAPK and Wnt-βCatenin pathway genes. Common alterations in the metastatic tumors include TP53 deletion/mutation (42%), AR amplification/mutation (38%), PTEN deletion/mutation (27%), RB1 deletion/mutation (20%), BRCA2 deletion/mutation (11%), FOXA1 mutation (11%) and SPOP mutation (4%). Among metastatic samples, tumors from pts with castration-resistant disease had higher CNA burden when compared to tumors from non-castration-resistant pts (0.31 vs. 0.19 fraction genome altered, p < 0.05, unpaired t-test), as well as higher rates of AR amplification/mutation (49% vs. 3%, p < 0.01, Fisher’s exact test). Conclusions: Genomic profiling of primary and metastatic prostate tumors is feasible with the clinical MSK-IMPACT sequencing assay and has identified actionable alterations in > 40% of patients. This is allowing for selective trial enrollment and further investigation of PC genomics. [Table: see text]
Effect of anti-GRP78 autoantibodies on prostate cancer progression through tissue factor procoagulant activity.
Authors: Al-Hashimi Ali , Shayegan Bobby , Austin Richard 
Published: February 2017

258 Background: Prostate cancer (PC) is characterized by increased prothrombotic state due to enhanced tissue factor (TF) expression/procoagulant activity (PCA). We and others observed that GRP78, a molecular chaperone, is expressed on the surface of PC cells where it functions as a signaling receptor to promote cell proliferation and survival. Further, exposure of GRP78 on the surface of PC cells stimulates the production of anti-GRP78 autoantibodies in PC patients. We have reported that binding of these autoantibodies to cell surface GRP78 enhances TF PCA. We hypothesize that this autoantibody/cell surface GRP78 complex interaction increase PC progression and that disruption of this complex would represent a viable target for the treatment of advanced PC. Methods: Wild type, TF knockdown DU145 cells, and NOD/SCID mouse model system was used to investigate the effect of anti-GRP78 autoantibodies on tumour growth. Protein expression was determined using western blotting and qRT-PCR. TF activity was determined using the TF PCA continuous assay. Blood samples from patients diagnosed with PC were obtained from the Ontario Tumour Bank and St. Joseph’s Hamilton. Results: Pre-prostatectomy patients demonstrated high levels of anti-GRP78 autoantibodies (60-100µg/ml) vs. healthy individuals (5-10µg/ml). These titres were significantly reduced 24-weeks post prostatectomy. We show here that anti-GRP78 autoantibodies upregulate TF and its PCA through a mechanism involving depletion of ER Ca2+ stores. This very effect on ER Ca2+ stores also caused activation of the unfolded protein response, a pro-survival cellular pathway. Furthermore, these autoantibodies were shown to accelerate tumour growth in a NOD/SCID mouse model. Finally, heparin and low molecular weight heparin were shown to interfere with the binding of these antibodies to cancer cells and prevent PC cell activation. Conclusions: We have identified the function of an agent in patients' blood, anti-GRP78 autoantibodies, that correlate with PC stage in patients and increase TF PCA and promote PC progression in mice. The effect of this autoantibody can be reversed using heparin, thus, this acts as a new potential therapeutic target for PC.