bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study
Authors: Martinelli Giovanni , Boissel Nicolas , Chevallier Patrice , Ottmann Oliver , Gökbuget Nicola , Topp Max S. , Fielding Adele K. , Rambaldi Alessandro , Ritchie Ellen K. , Papayannidis Cristina , Sterling Lulu Ren , Benjamin Jonathan , Stein Anthony 
Published: March 2017

PurposeFew therapeutic options are available for patients with Philadelphia chromosome–positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) −based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ALL.Patients and MethodsThis open-label phase II study enrolled adults with Ph+ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs).ResultsOf 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.ConclusionSingle-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph–ALL.
Quality of Survivorship in a Rare Disease: Clinicofunctional Outcome and Physical Activity in an Observational Cohort Study of 618 Long-Term Survivors of Ewing Sarcoma
Authors: Ranft Andreas , Seidel Corinna , Hoffmann Christiane , Paulussen Michael , Warby Ann-Christin , van den Berg Henk , Ladenstein Ruth , Rossig Claudia , Dirksen Uta , Rosenbaum Dieter , Juergens Herbert 
Published: March 2017

Purpose Significantly improved survival rates in patients with Ewing sarcoma have raised interest in accessing the quality of long-term survivorship. In this study, subjective and objective measurement tools, preclassified as physical or mental scores, were used to assess clinicofunctional outcome and physical activity after intensive bone tumor treatment. Methods Long-term outcome of 618 survivors from consecutive Ewing sarcoma trials was assessed by the Toronto Extremity Salvage Score, Short-Form Health Survey (SF-36), Brief Symptom Inventory (BSI), and Rosenberg Self-Esteem Scale questionnaires and by the accelerometric StepWatch 3 Activity Monitor. Prospective measurements were correlated retrospectively with standardized primary trial data. Results were compared with 316 nonrandom healthy peers by using effect sizes ( d). Median observation time was 12.9 years from primary diagnosis (range, 3.7 to 31.2 years). Results Absolute subjective scores were moderate to good for survivors. Compared with control subjects, unfavorable outcome was shown on physical Toronto Extremity Salvage Score, SF-36 Physical Component Summary, and BSI-Somatization scales (| d| ≥ 0.50; P < .01), in contrast to SF-36 Mental Component Summary, BSI-Anxiety, BSI-Depression, and Rosenberg Self-Esteem Scale mental scales (| d| ≤ 0.31). Survivors were less active than control subjects, as demonstrated by a step count difference of 1,742 steps per day ( d = −0.43; P < .01); however, on average, the recommended level for an active lifestyle was achieved (≥ 10,000 steps). Location of pelvic tumor was the major inferior disease-specific prognostic factor in physical scores ( P < .01), whereas nondisease-specific inferior factors in questionnaires were older age and female sex ( P < .01). Conclusion Survivors of Ewing sarcoma apparently returned to a normal life with minor limitations. Observed reductions in physical scores should be a focus in future research to optimize treatment strategies to reduce a negative impact on the quality of survivorship.
Defining predictors of early, intermediate, and late biochemical recurrence in men with clinically localized prostate cancer treated with minimally invasive radical prostatectomy.
Authors: Barreras Silvia Garcia , Nunes-Silva Igor , Sanchez-Salas Rafael , Secin Fernando P. , Srougi Victor , Baghdadi Mohammed , Barret Eric , Rozet Francois , Galiano Marc , Cathelineau Xavier 
Published: March 2017

113 Background: Follow up after radical prostatectomy should be tailored to clinical and pathologic characteristics. To determine predictive factors for early, intermediate and late biochemical recurrence (BCR) after minimally invasive radical prostatectomy (MIRP: lap and robot) in patients with localized prostate cancer (PCa). Methods: Prospective clinical, pathologic, and outcome data were collected for 6195 patients with cT1-3N0M0 PCa treated with MIRP at our institution from 2000 to 2016. None of them received neoadjuvant therapy. BCR was defined as PSA level greater than 0.2 ng/ml. Time to BCR was divided in terciles to identify variables associated with early ( < 12 months), intermediate (12-36 months) and late BCR ( > 36 months). Comparisons among groups were performed using ANOVA or Chi square test. Logistic regression models were built to determine risk factors associated with BCR at each time interval. Results: We identified 1148 (19%) patients with BCR. Median time to BCR was 24 months. Statistically significant differences were found between the groups concerning PSA preoperative, D’Amico risk, type of surgery, pT stage, pathological Gleason, positive margins and extracapsular extension. Multivariable logistic regression analysis showed preoperative PSA, positive nodes, positive surgical margins and laparoscopic surgery were associated with early BCR. Laparoscopic surgery was the only risk factor associated with intermediate term BCR. Significant predictors of late BCR included Gleason ≥ 7, ≥ pT3, positive surgical margins, lymph node dissection performance and laparoscopic surgery. Conclusions: Patients with high risk features like Gleason ≥ 7, ≥ pT3 and or positive surgical margins may develop late recurrence and deserve long term follow up. Identify patients with higher PSA and lymph node invasion has an important predictive role due to the risk of BCR within the first year. The association between laparoscopic technique and late BCR deserves further evaluation.
Whole-exome sequencing of single circulating tumor cells is a useful tool for studying the intrapatient genetic heterogeneity in metastatic prostate cancer.
Authors: Faugeroux Vincent , Lefebvre Celine , Pailler Emma , Pierron Valerie , Billiot Fanny , Marcaillou Charles , Tourlet Sebastien , Vielh Philippe , Dogan Semih , Rameau Philippe , Ngocamus Maud , Massard Christophe , Soria Jean-Charles , Fizazi Karim , Tibbe Arjan , Julien Sylvia , Loriot Yohann , Farace Francoise 
Published: March 2017

148 Background: Molecular characterization of metastatic castration resistant prostate cancer (mCRPC) is limited by tumor tissue availability. The analysis of circulating tumor cells (CTC) offers an attractive noninvasive surrogate option to analyze molecular alterations. We report whole exome sequencing (WES) of CTCs at the single cell level in mCRPC patients. Methods: Blood samples were drawn from 11 enzalutamide or abiraterone pre-treated mCRPC patients enrolled in the clinical program MOSCATO (NCT02613962). CTC enrichment, immunofluorescent detection and single cell isolation were performed using three methods (ISET filtration, CellSearch and the VyCap puncher system and RosetteSep enrichment) to obtain pools of 1-10 CTCs with distinct epithelial or mesenchymal phenotypes. After Whole Genome Amplification (WGA), WES was performed on the Illumina HiSeq 2000 platform. GATK Haplotype Caller enabled identification of germline polymorphisms from each patient in normal DNA, metastatic sample and CTCs in order to consider WGA induced bias. The detection of sSNV in tumor biopsies and CTCs was assessed with Mutect and IndelGenotyper respectively. Results: 189 WGA of CTC pools were performed. 34 pools of phenotypically different CTCs from 7 patients were selected and sequenced. Mean coverage of 51% was obtained at a sequencing depth of 10X. Allelic drop out was lower for CTC pools containing 5-10 cells. 17/34 (50%) CTC samples had shared sSNV with the paired tumor sample (range 0.35%-68%) Epithelial CTCs had more shared sSNV with metastatic biopsies than CTCs of other phenotypes but shared sSNV were also detected in large non epithelial CTC pointing out a high level of genetic heterogeneity between CTC. Overall, 89 deleterious protein-coding mutations were found only in pools of CTC, including mutations affecting oncogenic drivers such as MAPK1, HSP90AB1 or KDM5B. Conclusions: We present single cell WES of CTCs harboring distinct phenotypes. The detection of shared sSNV between CTC pools and corresponding biopsy could validate the use of CTCs as a liquid biopsy. The finding of sSNV specific to CTCs could offer additional data on tumor heterogeneity.
Survival outcomes for African-American (AA) vs matched Caucasian (CAU) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T (sip-T).
Authors: Quinn David I. , Freedland Stephen J. , Heath Elisabeth I. , Tutrone Ronald F. , McLeod David G. , Sheikh Nadeem Anwar , Chang Nancy N. , Sartor A. Oliver 
Published: March 2017

192 Background: Prostate cancer risk and mortality is higher in AA vs CAU men. In an analysis of three phase 3 mCRPC trials, AA pts appear to derive greater survival benefit with sip-T, an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC. AA pts on sip-T had a 30.7-month (mo) median overall survival (OS) benefit vs control (AUA 2012 P953), in contrast to a 4.1-mo OS benefit with sip-T vs control for all pts in IMPACT (NEJM 2010;363:411). As the prior analysis did not adjust for baseline differences between races, we matched AA to CAU pts on sip-T to better assess racial differences in sip-T benefit and cumulative antigen presenting cell (APC) activation, which correlates with OS (CII 2013;62:137). Methods: Data were from phase 3 mCRPC trials that randomized pts 2:1 to sip-T or control (D9901 [NCT00005947]; D9902A [NCT01133704]; IMPACT [NCT00065442]). Thirty-three AA sip-T pts were matched with 66 CAU sip-T pts based on predicted Halabi survival. Data were evaluated by the Kaplan-Meier method (event rates) and ANOVA (APC activation). Results: Median follow-up was 23.2 mos. AA pts on sip-T had a 20.6-mo longer median OS (45.3 mos; 95% CI 23.4–NE) vs CAU pts (24.7 mos; 95% CI 18.1–29.4) (HR = 0.49; 95% CI 0.26–0.91; p = 0.02). Median event-free survival (time to death or anticancer intervention [ACI]) was 10.7 mos for AA pts (95% CI 8.5–21.5) vs 8.7 mos for CAU pts (95% CI 6.6–11.5) (HR = 0.74; 95% CI 0.47–1.18; p = 0.20). Median time to next ACI was 23.5 mos in AA pts (95% CI 9.4–NE) vs 16.3 mos in CAU pts (95% CI 9.7–25.6) (HR = 0.78; 95% CI 0.42–1.43; p = 0.42). In AA pts, median APC activation was higher with sip-T infusion 1 vs CAU pts (7.0 vs 5.5, p = 0.004). Median cumulative APC activation over the three infusions was 27.7 (22.6–42.4, AA) vs 25.7 (21.5–33.9, CAU) (p = 0.083). Conclusions: Prior studies found sip-T provides OS benefit to both AA and CAU mCRPC pts. Herein, for men treated with sip-T, AA had longer survival, suggesting sip-T may provide greater OS benefit in AA. The basis for this may be biologic (greater APC activation). Further studies with larger sample sizes are needed to confirm if AA pts derive greater OS benefit from sip-T. Clinical trial information: NCT00005947; NCT01133704; NCT00065442.
The impact of TAS3681, a new type of androgen receptor antagonist, on aberrant AR signaling that drives tumor resistance to AR-targeted therapies by down-regulating full length and splice variant AR.
Authors: Kajiwara Daisuke , Minamiguchi Kazuhisa , Seki Masanao , Mizutani Hiroya , Yamamura Keisuke , Okajima Shigeo , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu 
Published: March 2017

197 Background: The treatment of castration-resistant prostate cancer (CRPC) has changed dramatically with the use of two new therapies, enzalutamide and abiraterone, directed at the androgen receptor (AR) signaling axis. However, eventually almost all patients relapse after these agents because of acquired resistance by a variety of mechanisms such as AR overexpression, the occurrence of AR mutations, or the induction of AR splice variants that confer ligand independent AR transactivation. TAS3681 is an oral pure AR antagonist with AR down-regulating activity. In this study, we investigated the effect of TAS3681 on several issues related to resistance to current AR-targeted therapy. Methods: VCaP cells transfected with wild-type AR-expressing vector, which overexpress AR, were treated with TAS3681 in the presence of androgen. Cells were harvested and luciferase activity was determined. For the analysis of F876L mutant AR, LNCaP cells stably expressing F876L AR protein were incubated with TAS3681 in the presence of androgen. The WST-8 assay was performed to measure cell viability. Prostate cancer cells expressing AR-v7 were treated with TAS3681, and full length (FL)-AR and AR-v7 protein levels were determined by Western blot. TAS3681 was orally dosed to confirm AR down-regulation in tumor and evaluate antitumor efficacy in AR-v7 positive CRPC tumor xenograft mouse model. Results: In prostate cancer (PCa) cells which overexpress AR, in contrast to enzalutamide, TAS3681 effectively suppressed AR transactivation and cell proliferation via AR down-regulation. TAS3681 effectively antagonized F876L mutant AR which confers resistance to cell growth inhibition by enzalutamide. Moreover, TAS3681 reduced both FL-AR and AR-v7 protein level in PCa cells in vitro and in vivo, and showed strong antitumor efficacy in AR-v7 positive xenografts. Conclusions: TAS3681 disrupts the aberrant AR signaling via a novel mechanism of action: pure AR antagonism plus down-regulation of full-length and splice variant AR. These findings suggest that TAS3681 has the potential to overcome resistance to current AR pathway target drugs.
A phase II study combining ipilimumab and degarelix with or without radical prostatectomy (RP) in men with newly diagnosed metastatic noncastration prostate cancer (mNCPC) or biochemically recurrent (BR) NCPC.
Authors: Autio Karen A. , Eastham James Andrew , Danila Daniel Costin , Slovin Susan F. , Morris Michael J. , Abida Wassim , Laudone Vincent Paul , Touijer Karim A. , Gopalan Anuradha , Wong Phillip , Curley Tracy , Dayan Erica Simone , Bellomo Lawrence P. , Scardino Peter T. , Scher Howard I. 
Published: March 2017

203 Background: Androgen deprivation therapy (ADT) does not completely eliminate disease in mNCPC or BRPC. We explored a multimodality treatment (tx) approach combining ADT with ipilimumab (ipi) with the aim of achieving no evidence of disease or complete elimination of disease, given the potential for cure seen with immunotherapy. Methods: Cohort A (Coh A) enrolled men with ≤ 10 bone metastases treated with induction of degarelix (deg) and ipi prior to RP and subsequent ipi q3 weeks x 3 and 8 months (mos) total of deg. Cohort B (Coh B) opened later and enrolled men with BRNCPC after RP with a doubling time ≤ 12 mos, and received ipi q3 weeks x 4 and 8 mos of deg. The primary endpoint was an undetectable PSA (<0.05) at 12 and 20 mos with non-castrate testosterone. Results: 16 pts (7 Coh A; 9 Coh B) were treated. No Coh A pts experienced immune related toxicities (irAE) that delayed surgery. 4/7 (57%) Coh A pts came off study for irAE, 1 (14%) for insurance reasons, and 2 (29%) completed all protocol requirements. In Coh B 6/9 (67%) pts have completed tx and entered follow-up. Conclusions: A combined modality approach with ipi 10mg/kg, ADT, and RP in mNCPC was associated with limiting toxicities, however 3mg/kg was better tolerated and more feasible in a BRNCPC cohort. One pt in Coh A (14%) had an undetectable PSA with testosterone recovery while evaluation of efficacy for Coh B is ongoing. The role for RP and other immunotherapeutic approaches in NCPC remain viable interests to the field. Clinical trial information: NCT02020070. [Table: see text]
Premature clinical trial discontinuation in all and genitourinary (GU) cancers in the era of immune checkpoint inhibitors (ICI).
Authors: Khunger Monica , Rakshit Sagar , Tullio Katherine , Galsky Matt D. , Grivas Petros 
Published: March 2017

394 Background: Clinical trial completion is critical for evaluating new therapies. Premature termination or withdrawal of clinical trials is common, impairs progress and results in waste of resources. We assessed features and reasons of early terminated and withdrawn cancer trials focusing on trials with ICI (anti-CTLA-4, anti-PD-1, anti-PD-L1). Methods: We reviewed all adult, intervention, cancer clinical trials registered in ClinicalTrials.gov from November 16, 2011 to April 16, 2015 to identify all early terminated and withdrawn trials. Reasons for termination were captured. Logistics regression model was used to identify factors associated with early termination or withdrawal. Discontinuation rate was compared between ICI and all trials (χ2); p < 0.05 was set as significant. Results: We identified 12875 clinical trials (35% industry-funded, 12% federal-funded; 772 in prostate and 386 in non-prostate GU cancers); 8.5% of all trials were prematurely terminated (5%) or withdrawn (3.5%); main reason for discontinuation was poor accrual (33%) followed by logistical reasons (26%). When comparing trials with ICI (n = 350) to all cancer trials, lower rate of termination or withdrawal was noted with ICI [5.4% vs 8.5%, p = 0.05]. Trials with ICI were less likely to discontinue due to poor accrual compared to all trials, but the difference was not significant (21% vs 33%, p = 0.4). Of the 1158 GU cancers trials, 75 (6.5%) were prematurely terminated and 56 (4.8%) withdrawn; reasons for discontinuation are shown in the table. Conclusions: Poor accrual represents the main cause of early termination of all cancer clinical trials. Premature termination/withdrawal rate appears lower in ICI trials which may be attributed to accrual differences. Clinical trial completion remains a high priority. [Table: see text]
Treatment utilization patterns for prostate cancer (PCa): An analysis from the National Cancer Database (NCDB).
Authors: Aragon-Ching Jeanny B. , Hussey Heather M. , Nguyen Hong , Chen Dechang , Henson Donald , Simmens Samuel J. 
Published: March 2017

99 Background: We previously reported the effects of the PSA screening guidelines on the patterns of diagnosis and treatment for PCa based on analyses from the NCDB dataset (Aragon-Ching et al., ASCO GU 2016). Given increasing use and advocacy for active surveillance, we now report on the treatment utilization patterns for PCa by facility type and overall incidence of active treatment (surgery or radiation), no treatment, or active surveillance by PCa stage using the NCDB dataset. Methods: Using a de-identified dataset acquired from NCDB from 1998 to 2012, treatment status of all 337,568 men for which information was available was tabulated according to whether active treatment, no treatment, or active surveillance (i.e. watchful waiting) was performed. Patient characteristics, stage, and treatment status by facility type was determined. Results: There were 1,802,596 patients diagnosed with prostate cancer between 1998 and 2012 in the NCDB. Of the 337,568 men for which treatment status was available, 92% received treatment, nearly 4% were under active surveillance, and another 4% did not receive any form of treatment or active surveillance. Of patients diagnosed with TNM Stage I and II PCa, only 7.5% and 2.22%, respectively, were followed under active surveillance. Overall, active surveillance was most utilized (n = 7,524; 5.7% of men) in academic research programs compared to other treatment facilities. Of the 310,898 men who received any form of active treatment, 193,889 men (62.3%) received surgery and 108,925 men (35%) received radiation. Conclusions: Active surveillance as a treatment modality comprised only a minority of patients who underwent treatment for PCa from 1998–2012, even among men with early Stage I and II Pca. Interestingly, the majority of the men who did receive active surveillance as their treatment option were treated at academic research programs, perhaps alluding to increased recognition and adherence to the PSA screening and active surveillance guidelines compared to other treatment facility types. Datasets including PCa patients beyond 2012 will be explored to further evaluate these changes in treatment modalities.
Humidity-mediated changes in an orb spider's glycoprotein adhesive impact prey retention time
Authors: Opell Brent D. , Buccella Katrina E. , Godwin Meaghan K. , Rivas Malik X. , Hendricks Mary L. 
Published: March 2017

ABSTRACT
Properties of the viscous prey capture threads of araneoid orb spiders change in response to their environment. Relative humidity (RH) affects the performance of the thread's hygroscopic droplets by altering the viscoelasticity of each droplet's adhesive glycoprotein core. Studies that have characterized this performance used smooth glass and steel surfaces and uniform forces. In this study, we tested the hypothesis that these changes in performance translate into differences in prey retention times. We first characterized the glycoprotein contact surface areas and maximum extension lengths of Araneus marmoreus droplets at 20%, 37%, 55%, 72% and 90% RH and then modeled the relative work required to initiate pull-off of a 4 mm thread span, concluding that this species' droplets and threads performed optimally at 72% RH. Next, we evaluated the ability of three equally spaced capture thread strands to retain a house fly at 37%, 55% and 72% RH. Each fly's struggle was captured in a video and bouts of active escape behavior were summed. House flies were retained 11 s longer at 72% RH than at 37% and 55% RH. This difference is ecologically significant because the short time after an insect strikes a web and before a spider begins wrapping it is an insect's only opportunity to escape from the web. Moreover, these results validate the mechanism by which natural selection can tune the performance of an orb spider's capture threads to the humidity of its habitat.