bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel live tumor cell diagnostic test utilizing biophysical and molecular biomarkers to assess local, advanced, and metastatic prostate cancer.
Authors: Knopf Kevin B. , Manak Michael S. , Su Wendell R. , Meyyappan Thiagarajan , Min Andrew , Saphirstein Robert J. , Hogan Brad J. , Whitfield Matt J. , Varsanik Jonathan S. , Foroohar Mani , Kella Naveen , Hernandez Ray , Rieger-Christ Kimberly M. , Sullivan Travis B. , Rashid Hani H. , Mouraviev Vladimir , Albala David , Chander Ashok C. , Sant Grannum R. 
Published: February 2017

211 Background: Over-treatment of prostate cancer affects 144,000 patients annually in the U.S. due to the inaccuracy of current diagnostics for risk stratification. Functional molecular and biophysical biomarkers combined with clinically actionable diagnostic platforms are used for evaluating the local invasiveness and metastatic potential of cells derived from biopsy. Such a diagnostic test may improve patient outcomes in low-to high-risk prostate cancers according to D’Amico’s definition. This study describes the development of a novel phenotypic diagnostic using a set of biomarkers measured with a proprietary live cell assay coupled with innovative machine vision algorithms for patient tumor samples using a unique microfluidic platform. Methods: We assessed 60 prostate cancer samples collected post radical prostatectomy (RP). We report the assay details for culturing live tumor cells ex vivo, enabling automated imaging of phenotypic biomarkers. The test is designed to sustain survival of prostate tumor cells from fresh biopsy/surgical samples for up to three days prior to analysis of phenotypic characteristics. Results: We show that this test distinguishes live normal and tumor cells via molecular and biophysical biomarkers. The primary biomarkers are calculated using objective machine vision algorithms and are used to derive secondary metrics termed “Metastatic Potential (MP) and Oncogenic Potential (OP)”. In comparing clinical measures with results of this test, concordance analysis show that OP and MP are statistically significant in distinguishing between Gleason 6 and Gleason 7 with 85% sensitivity and 80% specificity. Conclusions: This phenotypic diagnostic generates scoring metrics of MP and OP that correlate with 1) aggressive vs. indolent Gleason 6, 2) seminal vesicle invasion, 3) occurrence of margins after RP, 4) lymph node invasion and 5) systemic metastatic process. These results will further help stratify patient tumors to improve clinical decision-making in low to intermediate- and high-risk prostate cancer populations, and potentially avoid unnecessary surgery or radiation, ultimately leading to improved patient quality of life.
Activity of new agents (NAs) as third-line treatment in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) showing a primary resistance (PRes) to NAs-based second line therapy after docetaxel (DOC): Preliminary results from a multicenter Italian study.
Authors: Caffo Orazio , De Giorgi Ugo , Facchini Gaetano , Fratino Lucia , Gasparro Donatello , Basso Umberto , Alesini Daniele , Tucci Marcello , Ortega Cinzia , Verderame Francesco , Procopio Giuseppe , Lo Re Giovanni , Campadelli Enrico , Omarini Claudia , Donini Maddalena , Morelli Franco , Zucali Paolo A. , Sartori Donata , Conteduca Vincenza , Galligioni Enzo 
Published: February 2017

216 Background: The androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, abiraterone acetate (AA), cabazitaxel (CAB), and enzalutamide (ENZ). It is postulated that some mechanisms of resistance may be common to all NAs. This may be crucial in planning their sequential use, mainly when a PRes to one of them is observed. The present study assessed the activity of NAs in pts who previously experienced a PRes to another NA administered after DOC. Methods: We collected data of pts who received sequentially two NAs after DOC in 32 Italian hospital. For each pt we recorded the clinical outcomes of all treatments received after DOC. For the study purpose, we consider with PRes all pts progressing within 3 months after second line NA start. All other pts were considered as without PRes. Results: A consecutive series of 271 mCRPC pts, median age 71 yrs (46-91), with bone (89%), nodal (56%) or visceral (19%) mets, was collected. All pts received NAs as second line after DOC (AA 54% – CAB 34%– ENZ 12%) and 54 (20%) showed a PRes. Among these, third line treatment [AA (31%), CAB (42%), and ENZ (27%)], produced a biochemical and an objective response rate of 11% in both cases, with a median progression free survival (PFS) and a median overall survival (OS) of 4 mos and 8 mos, respectively. No statistically significant differences were observed in terms of clinical outcomes on the basis of NA sequences (see Table). Conclusions: It appears from this preliminary data, that the activity of NAs in pts showing a PRes to second line NAs is very limited, regardless the NA is administered. [Table: see text]
Pathologic correlation of 89Zr-Df-IAB2M antiprostate-specific membrane antigen (PSMA) minibody in patients with metastatic prostate cancer.
Authors: Morris Michael J. , Solomon Stephen Barnett , Durack Jeremy C. , O' Donoghue Joseph A. , Lyashchenko Serge K. , Shutian Ruan , Carrasquillo Jorge A. , Lewis Jason Stuart , Martinez Danny F. , Parada Nicole A. , Keppler Jennifer , Wu Anna , Reuter Victor E. , Weber Wolfgang , Scher Howard I. , Larson Steven M. , Pandit-Taskar Neeta 
Published: February 2017

220 Background: IAB2M is a novel anti-PSMA minibody (Mb) based on the humanized J591 antibody that targets the extracellular domain of PSMA. The Mb has been engineered to remove Fc-Rn interactions and reduce the molecular weight relative to J591. The result is faster blood pool clearance, for a more favorable imaging schedule, while retaining bivalent targeting of PSMA. We have previously reported on the pharmacokinetics, dosimetry, and lesion uptake of IAB2M(Pandit-Taskar et al, WMIS 2014). Here we report the correlation between imaging and pathology of biopsies of PSMA avid lesions. Methods: Following standard imaging (SI) of CT/MRI, bone scintigraphy (BS), and FDG PET, 5 mCi of 89Zr-Df-IAB2M was administered intravenously. Escalating minibody doses of 10, 20, and 50 mg were delivered, with cohort expansion at 10 and 20 mg. Whole body PET/CT scans were serially performed at various time points:1-2 h, 24 h, 48 h, and 72-144 h post injection. Metastases identified on PET were confirmed, where possible, with bx’s in the following preference: concordant IAB2M and FDG positivity, IAB2M, and FDG mismatch, or a mismatch between SI and any PET. Results: 24 patients (pts) with metastatic prostate cancer were scanned (11 at 10, 7 at 20, and 6 at 50 mg Mb doses). A total of 15 bxs (7 soft tissue, 8 bone) were performed on 14 pts; the histopathologic correlation is summarized in the table below. 13 lesions were identified by IAB2M, 11 by FDG, and 14 by SI. Of these, 12/13 (92.3%), 10/11 (90.9%), 12/14 (85.7%) were biopsy positive for cancer, respectively. 2 bone lesions were not identified by IAB2M, evident on other imaging modalities, and were both neg by bx. Overall bx concordance (pos/pos, neg/neg) with imaging was: IAB2M 14/15 (93%) vs. BS/CT 13/15 (86%) vs. FDG 12/15 (80%). Conclusions: An ongoing analysis of IAB2M imaging showed a high concordance with pathologic findings in patients with metastatic prostate cancer. Clinical trial information: NCT01923727. [Table: see text]
Dose escalation of five-fraction SABR for prostate cancer: Biochemical outcome and toxicity comparison of two prospective trials.
Authors: Musunuru Hima Bindu , Quon Harvey Charles , Zhang Liying , Cheung Patrick , Tang Colin I , Pang Geordi , Mamedov Alexandre , D'Alimonte Laura , Deabreu Andrea , Loblaw D. Andrew 
Published: February 2017

224 Background: To compare the biochemical outcomes and toxicities of two different 5 fraction stereotactic ablative body radiotherapy (SABR) schedules for the treatment of localized prostate cancer. Methods: Two sequential phase I/II studies of 5-fraction SABR for the treatment of low and intermediate risk (LR and IR) prostate cancer have been conducted. In the first trial, 84 LR patients(pts) received 35 Gy in 5 fractions, once per week over 29 days (Group 1). In the second trial, 30 pts (18 LR, 11 IR) received 40 Gy in 5 fractions, once per week over 29 days (Group 2). Treatment was delivered to the prostate with intensity modulated radiotherapy using daily image guidance and a 4mm (Group 1) or 5 mm (Group 2) CTV-PTV margin. PSA nadir and bRFS(nadir+2 definition) were compared between the two groups. Acute (CTCv3.0), late (RTOG) and cumulative toxicity for late grade ≥ 2 GU/GI toxicities were also compared. Results: Median follow up was 74 (IQR 67-81) and 36 (IQR 32-39) months. Median PSA nadir was 0.4 ng/ml and 0.3 ng/ml. Time to PSA nadir was 54 and 32.5 months. 44.0% in group 1 and 30% in Group 2 experienced benign PSA bounce. There were 3 and 0 PSA failures in Groups 1 and 2. 2-, 4- and 6-year bRFS was 100%, 98.7% and 95.9% and 100%, 100% and not reached in groups 1 and 2, respectively (p=0.91). The only acute grade 3 toxicity was noticed in Group 1 (1 pt, GU). Late grade 4 GI toxicity was noted in Group 1 (1 pt, GI, fistula). Up to 4 years of follow-up, Group 2 pts have had a greater percentage of grade 2+ cumulative GU (5.0% vs 24.2%) and GI (7.6% vs 26.2%) toxicities. Conclusions: Pts receiving a dose escalated SABR had slightly lower PSA nadir and similar bRFS - longer follow up is needed to better estimate biochemical outcomes in Group 2. There seemed to be a greater risk of grade 2 toxicities in the higher dose cohort but grade 3+ toxicities were not increased. Quality of life analyses will be presented separately. Clinical trial information: NCT01578902 , NCT01146340 .[Table: see text]
Current era clinical outcomes of castration-resistant prostate cancer in real-life population study in Quebec, Canada.
Authors: Rocha Joice , Vanhuyse Marie , Aprikian Armen G. , Cury Fabio L. , Dragomir Alice 
Published: February 2017

226 Background: Prostate cancer (PCa) death is mainly due to castration-resistant PCa (CRPC) which results from disease progression despite androgen ablation therapy (ADT). Little is known about clinical outcomes and trends of real-life CRPC management in the present era, which has become very complex. Our study aimed to analyze healthcare services use, clinical outcomes and survival trends in real-life management of CRPC in Quebec, Canada. Methods: The study cohort consisted of 7,123 patients which shown evidence of CRPC from January/2001 to July/2013, selected from the public healthcare insurance programs the Régie de l’Assurance Maladie du Québec (RAMQ) databases. Survival was evaluated by Kaplan-Maier and the difference in survival between pre-/post-docetaxel (Doc) (2002-2005 vs 2008-2011) era by log-rank test. The association between Doc exposure and survival was evaluated by Cox proportional hazards model adjusted for several co-variables. Results: Chemotherapy was offered to 17% of patients, while 45% were kept on maximal androgen blockade (MAB) alone, or offered Abiraterone (3%). Androgen targeted therapies (MAB or Abiraterone) were the treatment of choice for the elderly population (mean age 78.8 and 78 ±7, respectively) while chemotherapy was offered to younger patients (mean age 72 ±7.3). Survival rates at 1 and 2 years after the initiation of chemotherapy were 52% and 26% in post-Doc era vs 46% and 17% in the pre-Doc period. In patients receiving first line chemotherapy only, hospitalization due to PCa was a poor prognostic predictor (HR: 2.0; 95%CI: 1.5-2.6), as expected. In addition among patients without previous hospitalization the risk of death was higher in the pre- vs post-Doc era (HR: 1.7 CI: 1.003-2.851). Conclusions: Patient age seems to be a strong determinant in CRPC therapy selection. In patients without serious complications leading to hospitalization, survival was greatly improved in the post-Doc era. Our data also supports that patients older than those in the TAX327 trial (72 vs 68) may equally benefit from chemotherapy. This is encouraging as we hope to observe comparable results for new approved therapies for CRPC.
Treatment patterns of new metastatic castration-resistant prostate cancer (mCRPC) therapies: Real-world evidence from three datasets.
Authors: Ellis Lorie , Lafeuille Marie-Helene , Gozalo Laurence , Lefebvre Patrick , Malangone-Monaco Elisabetta , Wilson Kathleen , Foley Kathleen A. , McKenzie R. Scott 
Published: February 2017

228 Background: Little information exists regarding the sequences in which new mCRPC therapies with evidence of survival benefits are used. This study aims at describing the sequence of mCRPC medication use as observed in 3 healthcare datasets. Methods: Healthcare claims datasets (Dataset #1 and #2) and a community oncology electronic medical record (Dataset #3) were used to identify PC patients with ≥ 1 claim for a study drug (abiraterone acetate--AA, cabazitaxel--CAB, docetaxel – DOC, enzalutamide – ENZ, and sipuleucel T – SIP) occurring after 9/1/2012. The index date was the 1st study drug claim. Patients were excluded if a study drug claim occurred prior to 9/1/2012. Descriptive statistics summarized the proportion of patients receiving one vs. two or more lines of therapy. The prevalence of 1st line therapy and of 1st to 2nd-line sequences was analyzed. Results: Analysis of 3 unique datasets with > 5,900 PC patients revealed most patients received a single line of therapy. AA and DOC were the most common 1st line agents. The five most-prevalent 1st- to 2nd-line sequences identified in each database are shown in the table below. The most commonly observed 1st- to 2nd-line sequences were AA-ENZ, AA-DOC, and DOC-AA. Conclusions: Real world treatment selection for 5 mCRPC medications was consistent across 3 datasets. The majority of PC patients had a prescription/claim for a single agent. AA and DOC were the most commonly selected 1st line treatments. A 2nd-line agent was observed in 14-33% of patients. Similar patterns of 1st-2nd line sequences were observed between datasets. Further research is warranted with longer follow-up and consideration of other treatment interventions. [Table: see text]
Pharmacokinetics, activity, and safety of ODM-201 in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: An open-label phase I trial with long-term extension.
Authors: Massard Christophe , Penttinen Heidi , Bono Petri , Vjaters Egils , Lietuvietis Vilnis , Tammela Teuvo L. J. , Vuorela Annamari , Nykänen Pirjo , Pohjanjousi Pasi , Fizazi Karim 
Published: February 2017

230 Background: The open phase I trial, ARAFOR, with long-term extension evaluated pharmacokinetics (PK), antitumor activity and safety of ODM-201 in chemotherapy-naïve patients with progressive mCRPC. Methods: PK phase: Patients received one 600 mg dose of ODM-201 capsules (6 x 100 mg) in fed state and one dose of either tablet formulation (TabA or TabB, 2 x 300 mg) in fed and fasted state in random order. Extension: Patients received ODM-201 600 mg (capsule) twice daily until disease progression/ intolerable adverse event (AE). A data cut-off date Apr 4, 2014 was used for analyses. Results: 30 patients were enrolled in PK and treated in the extension phase. Baseline characteristics: median age 68 yrs, ECOG score 0 in 67%, and ECOG 1 in 33% patients, median PSA 18.2 ng/mL. Median time from PC diagnosis to start of ODM-201 treatment was 39 months. Median time on ODM-201 treatment was 9.5 months (trial is on-going). ODM-201 plasma concentration–time curves were similar for the capsule, TabA, and TabB at fed state. Median tmax at fed state was longer than in fasted state (5–6 h vs. 4 h). Absorption was slower and plasma exposure about 2-fold greater at fed state compared to fasted state (AUCt, AUC¥ and Cmax values). All 30 patients completed the first 12 weeks of the extension phase. Prostate-specific antigen (PSA) responses (≥50% reduction from baseline) were seen in 25 (83%) patients (PSA reductions ≥90% in 9 [30%] patients). At 12 weeks, RECIST responses in soft tissue were noted in 6 patients (29%) and stable disease in 13 (62%) patients, 3 (11%) had improvement in skeletal metastases and 18 (67%) stabilised bone disease. 21 (70%) reported at least 1 AE, and treatment-related AEs occurred in 6 (20%) patients. No treatment-related AEs of grade 2 or higher were reported. Conclusions: Tablet and capsule formulations showed comparable single-dose pharmacokinetics. Dose level of 600 mg twice daily (capsule) showed significant antitumor activity and had a favourable safety profile. Updated results from the extension phase will be presented. A phase 3 ARAMIS trial at a dose of 600 mg twice daily in men with non-metastatic CRPC is currently ongoing. Clinical trial information: NTC01784757.
Identification of susceptibility loci in hereditary prostate cancer families using copy number variation and linkage analysis.
Authors: Ledet Elisa M. , Bailey-Wilson Joan , Sartor Oliver , Li Marilyn M. , Mandal Diptasri 
Published: February 2017

232 Background: Family history is one of the most significant predictor of prostate cancer risk. With approximately 10% of prostate cancer cases attributable to inheritable genetic factors. However, disease gene identification for prostate cancer has been extremely challenging due to both disease and genetic heterogeneity. Therefore, the goal of this study was to employ an array of genetic tools in order to characterize germline variants in seven high-risk families with prostate cancer. Methods: To overcome the effects of ethnic disparity, genetic heterogeneity, incomplete penetrance, and missing heritability, we utilized a comprehensive approach that combines both array comparative genomic hybridization (aCGH) analysis and linkage analysis to identify genetic components of prostate cancer. Seven prostate cancer cases were studied using aCGH to search for germ-line copy number variants (CNVs) associated with hereditary prostate cancer. The study subjects were from 7 large, high-risk, clinically homogenous families with European ancestry from Southern Louisiana. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. Results: Three novel regions of CNVs were identified: 16q23, 11q22, and 2q22 in all 7 prostate cancer cases from high-risk families. Both model-based and model-free linkage analyses were performed on 4 of the most informative families (≥5 prostate cancer patients per family). Suggestive evidence of linkage was obtained at 2q14 (HLOD score of 1.94). Using aCGH, a 68 kb duplication was observed in this region in all 7 hereditary prostate cancer cases. Conclusions: These genetic findings, which were identified in multiple large, well-characterized families, provide new insight into hereditary prostate cancer. A combination of future fine mapping of the 2q14 region in a larger cohort of patients, confirmation of these novel CNVs in additional subjects, and use of next-generation sequencing approaches to search for potential disease-associated genetic alterations are needed to provide further characterization of these prostate cancer associated susceptibility loci.
Next-generation sequencing of circulating exosomal RNA from metastatic castrate-resistant prostate cancer patients.
Authors: Ledet Elisa M. , Gambhira Ratish , Dotiwala Aryeneesh , Mandal Diptasri , Sartor Oliver 
Published: February 2017

233 Background: PCa has proven to be an extraordinarily complex disease, with both genetic and phenotypic heterogeneity. Exosomes are membranous nano-sized (50-100nm) vesicles derived from both normal and tumor cells, and function in cell-to-cell communication. These vesicles and their nucleic acid cargo may serve as a peripheral biomarker for genetic risk assessment of PCa prognosis and therapeutic response. The goal of this study was to characterize exosome derived RNA (exoRNA) isolated from blood of metastatic CRPC patients. Methods: Blood samples from 18 consented clinically annotated mCRPC patients and 1 normal control; exosomes were isolated with ultracentrifugation and exoRNA extracted. Following library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data pre-possessing including alignment, duplicate removal, normalization and variant calling. Visualization and differential analyses were performed with SNP & Variation Suite v8.x. Results: Through preliminary analyses we identified 39 genes commonly expressed in the exosomes of these mCRPC patients. These include PDPK1, USP9X, MAGI2, HMGA2 and PTGFR all of which have been previously expressed in prostate cancer. In exoRNA there is evidence of extensive chromosomal rearrangement resulting in a myriad of gene fusions and isoforms. A diverse variety of lcnRNA, ncRNA and miRNA were also identified in circulating exosomes. Differential expression analyses will be presented. PCR validation is ongoing. Conclusions: The identification of PCa associated transcripts in blood derived exosomes provide evidence that exosomes and exosomal cargo may serve as biomarker in CRPC patients. Exosomes and exoRNA may provide otherwise unattainable insight into tumor evolution and disease progression. Additional studies evaluating the clinical relevance and prognostic value of exosomal RNA will be critical for biomarker development.
Characterization of therapies and timelines for men with prostate cancer-specific mortality.
Authors: Steinberger Allie E. , Ledet Elisa M. , Luk Eric , Cotogno Patrick , Stolten Michael , Desmond Daniel , Silberstein Jonathan L. , Sartor Oliver 
Published: February 2017

239 Background: Careful study of treatments in men with prostate cancer (PCa)-specific mortality is scant in non-trial settings. We sought to examine the characteristics and use of selected therapies in men dying from PCa, beginning from the time of diagnosis. Unique herein is the unequivocal attribution of PCa death by a single experienced clinician. Methods: Patients dying from PCa at Tulane Cancer Center from 2008 to 2014 (n=96) were studied through retrospective chart reviews. All patients died of metastatic, castrate-resistant disease (mCRPC). Results: The median age at diagnosis for the deceased cohort was 66 years (95% CI: 64-68 years); 29% of patients initially presented with metastatic PCa. 59% of patients had definitive primary therapy (radical prostatectomy or radiation). Though most men died prior to availability of the newer FDA-approved agents, patients received a median of 7 (range: 1-14) therapies. Median survival was 60 months (95% CI: 45.8-74.2 mo) after diagnosis with a median PSA pre-death of 171 (range: 0-3530) and median age at death of 73 years (95% CI: 71-75 years). At death, 4% of men had a PSA < 4 and 20% of men had a normal LDH (< 241 U/L). Distant metastatic disease at diagnosis was a significant predictor of death (HR=4.33, p<0.001) while definitive primary therapy was a significant predictor of survival (p<0.001). Median survival for patients presenting with metastases was 39 months (range: 5-213) compared to 82.5 months (range: 6-269) for localized disease (p < 0.001). Definitive therapy, vs. none, was associated with a median survival of 81.5 months vs. 47 months (p<0.001). Of the cohort, 48% received docetaxel before death; 49% received abiraterone, 10.4% received enzalutamide, 13.5% radium-223 and 15.6% sipuleucel-T. The only significant difference between docetaxel and non-docetaxel groups was median age of diagnosis at 62 and 71, respectively (p=0.002). Conclusions: This retrospective analysis provides initial views that clarify characteristics of men dying from PCa as well as the therapies they received before death. More data is needed in multi-institutional settings to confirm these findings. Given the evolving landscape for mCRPC treatments, therapeutic choices will change over time.