Citations

Endogenous female sex hormones influence muscle sympathetic nerve activity (MSNA), a regulator of arterial blood pressure and important factor in hypertension development. Although ≈80% of American women report using hormonal contraceptives sometime during their life, the influence of combined oral contraceptives (OCs) on MSNA and systemic hemodynamics remains equivocal. The goal of this study was to determine whether women taking OCs have altered MSNA and hemodynamics (cardiac output and total peripheral resistance) at rest during the placebo phase of OC use compared with women with natural menstrual cycles during the early follicular phase. We retrospectively analyzed data from studies in which healthy, premenopausal women (aged 18–35 years) participated. We collected MSNA values at rest and hemodynamic measurements in women taking OCs (n=53; 25±4 years) and women with natural menstrual cycles (n=74; 25±4 years). Blood pressure was higher in women taking OCs versus those with natural menstrual cycles (mean arterial pressure, 89±1 versus 85±1 mm Hg, respectively; P =0.01), although MSNA was similar in both groups (MSNA burst incidence, 16±1 versus 18±1 bursts/100 heartbeats, respectively; P =0.19). In a subset of women in which detailed hemodynamic data were available, those taking OCs (n=33) had similar cardiac output (4.9±0.2 versus 4.7±0.2 L/min, respectively; P =0.47) and total peripheral resistance (19.2±0.8 versus 20.0±0.9 U, respectively; P =0.51) as women with natural menstrual cycles (n=22). In conclusion, women taking OCs have higher resting blood pressure and similar MSNA and hemodynamics during the placebo phase of OC use when compared with naturally menstruating women in the early follicular phase.

Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI‐1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI‐1 was extended by a 2‐year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI‐2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β‐amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau‐mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [ 18 F]‐fluorodeoxyglucose‐PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low‐cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α‐syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β‐amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating‐sum of boxes further reduced sample sizes; (7) the pioneering of genome‐wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU , and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI‐like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease‐modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.

Abstract Background: Etirinotecan pegol (EP) is the first long-acting topoisomerase 1-inhibitor providing sustained level of active metabolite that concentrate in the tumor for an entire chemotherapy cycle. In a Phase 2 study (Lancet Oncology 2013), EP demonstrated a 29% overall response rate in patients with metastatic breast cancer, leading to the Phase 3 global BEACON study in this population. Detection of circulating tumor cells (CTCs) using immunomagnetic EpCAM-based methods have been conceptually accepted as a "liquid tumor biopsy". To circumvent the limited recovery of CTCs these methods provide for molecular profiling applications, we isolated CTCs based on an antibody-independent, continuous flow dielectrophoresis (DEP) technology (ApoStream®). We developed quantitative multiplex immunofluorescent assays for target-specific pharmacodynamics (PD) biomarkers for EP in CTCs isolated pre- and post-treatment. Here we present the distribution of the PD biomarkers in CTC samples collected from BEACON patients. Methods: Donation of blood samples for CTC analysis was voluntary. BEACON patients participating in the substudy had serial (pre-dose, Cycle 2 Day 1, Cycle 4 Day 1, End of Treatment) 7.5-mL whole blood samples drawn in EDTA tubes and shipped ambient to ApoCell (Houston, TX) within 96 hrs for processing. PBMCs were separated by Ficoll® gradient, and CTCs were isolated using ApoStream® technology. Isolated cells were deposited on three slides and stained for DAPI, CD45, and cytokeratin markers, as well as 2-3 of the seven PD markers, and analyzed by iCys® laser scanning cytometer equipped with image analysis software. CTC count, mean fluorescence intensity (MFI) of PD biomarkers, and % marker-positive cells were analyzed for their distribution. Results: 75% of the 852 BEACON patients participated in the CTC substudy, yielding 649 pre-treatment CTC samples. As of Mar14, 538 Cycle 2 Day 1, 281 Cycle 4 Day 1, and 394 End of Treatment samples were collected. 98% of pre-treatment blood samples were successfully processed. 97% had detectable CTCs, with a median of 504 CTCs (interquartile range: 128-1432). PD markers could be analyzed in 83-92% of samples after implementing a minimum requirement of 10 CTCs analyzed. Staining was positive for Top1, Top2, μH2Ax, Rad51, ABCG2, Ki67, and TUNEL in 82%, 71%, 14%, 30%, 20%, 56%, and 94% of samples, respectively. Percent of marker-positive cells varied from 0.2-69%, with 6- to 37-fold interquartile ranges. Median MFI in these cells varied between 25x103 and 100x103, with 1.2- to 1.6-fold interquartile ranges. Conclusions: CTC collection was successfully incorporated into the BEACON study, with 75% patient participation. CTC detection rate using ApoStream® was high, permitting evaluation of biomarkers at baseline and over time. EP target-specific PD biomarkers can be measured in CTCs isolated from patients participating in BEACON and will be assessed for their potential to predict clinical response. Final BEACON efficacy and safety results are expected in early 2015, which will allow further analysis of CTCs with patient outcome (response, PFS, OS) and change in CTCs at time of progression. Citation Format: Edith A Perez, Katie Caygill, Alison L Hannah, Javier Cortes, Ahmad Awada, Joyce O'Shaughnessy, Christopher Twelves, Hope Rugo, Seock-Ah Im, Kenna Anderes, Darren W Davis, Ute Hoch. Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-03.

Because Model for End‐Stage Liver Disease (MELD) scores at the time of liver transplantation (LT) increase nationwide, patients are at an increased risk for delisting by becoming too sick or dying while awaiting transplantation. We quantified the risk and defined the predictors of delisting or death in patients with cirrhosis hospitalized with an infection. North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) is a 15‐center consortium of tertiary‐care hepatology centers that prospectively enroll and collect data on infected patients with cirrhosis. Of the 413 patients evaluated, 136 were listed for LT. The listed patients' median age was 55.18 years, 58% were male, and 47% were hepatitis C virus infected, with a mean MELD score of 2303. At 6‐month follow‐up, 42% (57/136) of patients were delisted/died, 35% (47/136) underwent transplantation, and 24% (32/136) remained listed for transplant. The frequency and types of infection were similar among all 3 groups. MELD scores were highest in those who were delisted/died and were lowest in those remaining listed (25.07, 24.26, 17.59, respectively; P < 0.001). Those who were delisted or died, rather than those who underwent transplantation or were awaiting transplantation, had the highest proportion of 3 or 4 organ failures at hospitalization versus those transplanted or those continuing to await LT (38%, 11%, and 3%, respectively; P = 0.004). For those who were delisted or died, underwent transplantation, or were awaiting transplantation, organ failures were dominated by respiratory (41%, 17%, and 3%, respectively; P < 0.001) and circulatory failures (42%, 16%, and 3%, respectively; P < 0.001). LT‐listed patients with end‐stage liver disease and infection have a 42% risk of delisting/death within a 6‐month period following an admission. The number of organ failures was highly predictive of the risk for delisting/death. Strategies focusing on prevention of infections and extrahepatic organ failure in listed patients with cirrhosis are required. Liver Transpl 21:881‐888, 2015. © 2015 AASLD.

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.