Citations

Abstract INTRODUCTION Patient derived xenografts (PDX) may better reflect individual patient (pt) tumor biology; however, the feasibility of collecting PDX from percutaneous tumor biopsies (PTB) in the neoadjuvant setting is unknown. Furthermore, drug response phenotypes observed in PDX have not been prospectively compared to the corresponding pt clinical outcomes. METHODS The Breast Cancer Genome Guided Therapy Study (BEAUTY) is a prospective Mayo study of pts with high-risk breast cancer treated with neoadjuvant weekly paclitaxel (T) +/- trastuzumab followed by anthracycline based chemotherapy. PTB (at baseline) and residual surgical tissue (after all chemotherapy) are obtained for next generation sequencing (NGS) and PDX. Tumor biopsies (1-2 cores from 14 gauge needle) were implanted with Matrigel <1 hour of collection in the flanks of NOD-SCID or NSG mice. Low dose estradiol was supplemented in the drinking water. Primary outgrowth rate was defined as PDX tumor volume >50 mm3. Take rate was defined as development of at least 1 stably transplantable xenograft line/pt. To determine whether clinical T response assessed by MRI corresponded with in vivo T response, pretreatment PDX from 5 pts were injected into NOD-SCID mice (20 mice per pt PDX) and when tumors reached 100-200mm3, mice were randomized to no treatment vs T (20 mg/kg, ip. every 3-4 days). Two of these 5 patients had a MRI response defined as >30% decrease in longest lesion. RESULTS Pretreatment PTB from 81 unique pts were implanted in 251 mice (2-4 mice/pt). PDX outgrowth rates were 33.3% (27/81 pts) and 22 stable PDX were established (overall take rate 27.2%). Take rates were as follows: triple negative breast cancer (46%; 13/28); HER2 (27%; 6/22), Luminal B (13%; 3/22), and luminal A (0%; 0/9). Residual surgical tumor (after all treatment) from 17 pts was injected into 85 mice (average 5 mice/pt) and the initial outgrowth rate was 23% (4/17) with 3 stably transplantable lines established. PDX, derived from pretreatment PTB of 5 pts (2 responders and 3 non-responders), were assessed for in vivo T response. The size of the T treated group was significantly smaller than the no treatment group for the PDX derived from the 2 clinical responders, with complete disappearance of tumor by 18 days. In contrast, the PDX derived from the 3 clinical non-responders had no evidence for T response. CONCLUSIONS We have demonstrated the feasibility of using PTB to establish PDX in a prospective neoadjuvant clinical study and have demonstrated similar T drug response phenotypes in in the PDX as seen in the corresponding pt. These data suggest that PDX generated prospectively may be useful for biomarker validation and the development and individualization of new drug therapy. Funded by the Mayo Clinic Center for Individualized Medicine and the Mayo Clinic Cancer Center Citation Format: Jia Yu, Ping Yin, Bowen Gao, Jason P. Sinnwell, Ann M. Moyer, Daniel W. Visscher, Amy L. Conners, Travis J. Dockter, Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Hugues Sicotte, Douglas W. Mahoney, Steven N. Hart, Peter T. Vedell, Poulami Barman, Katie N. Jones, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Eric D. Wieben, James N. Ingle, Zhenkun Lou, Gianrico Farrugia, Richard Weinshilboum, Matthew P. Goetz, Judy C. Boughey, Liewei Wang. Feasibility of using percutaneous tumor biopsies from a prospective neoadjuvant breast cancer study to develop patient derived xenografts and assess in vivo chemotherapy sensitivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1195. doi:10.1158/1538-7445.AM2014-1195

AbstractObjectivesChest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR‐proADM) in prediction of mortality and major adverse cardiac events (MACE).MethodsThis was a subanalysis of the CHOPIN study, a 16‐center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6‐month all‐cause mortality and the secondary endpoint was 30‐day and 6‐month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure.ResultsMR‐proADM performed similarly to troponin (cTnI; c‐statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR‐proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6‐month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR‐proADM, history of coronary artery disease (CAD), and hypertension were predictors of short‐term MACE, while history of CAD, hypertension, cTnI, and MR‐proADM were predictors of long‐term MACE.ConclusionsIn patients with chest pain, MR‐proADM predicts mortality and MACE in all‐comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses‐generating and future prospective studies to identify its utility in risk stratification should be considered.

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P <0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P =0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P =0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P =0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00987415.

BACKGROUNDOur institutional policy allows patients who are scheduled for elective surgery with no history of a pregnancy or blood transfusion in the preceding 3 months to have a presurgical sample (PSS) collected and tested up to 56 days before their scheduled surgery; however, our PSS TS completion rate in eligible patients before the morning of surgery was 83%. In 2011, a team was charged to develop a standardized process along with other process improvements while ensuring no increase in transfusion‐related events.STUDY DESIGN AND METHODSThe team followed the DMAIC framework in appraising the effectiveness and efficiency of the current state process including baseline data collection such as PSS TS completion rate, number of eligible patients needing a PSS TS on the day of surgery, benchmarking, SSBO utilization, and future state mapping.RESULTSFirst quarter (Q1) 2011 versus Q1 2012 postimplementation results showed significant improvements of the process including a 53% decrease in PSS TS on the day of surgery; a 13% increase in PSS TS completion before the morning of surgery; a 26% reduction in total XM RBCs; and a 58.8% reduction in XM RBCs not issued, plus a 47% decrease in RBC wastage. Q1 2011 versus Q1 2013 showed a 41% reduction in total XM RBCs and an 88.4% reduction in XM RBCs not issued but overall RBCs issued versus returned increased slightly and represents a future opportunity for improvement.CONCLUSIONSThe redesigned, transformational process eliminated SSBO and improved ordering process and PSS TS completion rate as well as blood product ordering and utilization.

Wake-up stroke, defined as the situation where a patient awakens with stroke symptoms that were not present prior to falling asleep, represents roughly 1 in 5 acute ischemic strokes and remains a therapeutic dilemma. Patients with wake-up stroke were excluded from most ischemic stroke treatment trials and are often not eligible for acute reperfusion therapy in clinical practice, leading to poor outcomes. Studies of neuroimaging with standard noncontrast computed tomography (CT), magnetic resonance imaging (MRI), and multimodal perfusion-based CT and MRI suggest wake-up stroke may occur shortly before awakening and may assist in selecting patients for acute reperfusion therapies. Pilot studies of wake-up stroke treatment based on these neuroimaging features are promising but have limited generalizability. Ongoing randomized treatment trials using neuroimaging-based patient selection may identify a subset of patients with wake-up stroke that can safely benefit from acute reperfusion therapies.

Thyroid hormone excess is associated with increased energy expenditure. The contributions of increases in spontaneous physical activity and nonexercise activity thermogenesis (NEAT) to this effect have not been defined. To address the hypothesis that hyperthyroidism is associated with increased spontaneous physical activity and NEAT, we rendered rats hyperthyroid by using continuous infusion of high-dose triiodothyronine for 14 days and measured the effects on physical activity and NEAT. On day 14, in the hyperthyroid group the mean ± SD triiodothyronine concentration was 755 ± 137 (range 574–919) ng/dl and in the control group 59 ± 0.5 (58–59) ng/dl. Over the 14-day treatment period, mean spontaneous physical activity increased in the hyperthyroid rats from 24 ± 7 to 36 ± 6 activity units (AU)/min; P < 0.001 but did not increase in the controls (23 ± 7 vs. 22 ± 4 AU/min). Also, over the 14-day period, daily NEAT increased in the hyperthyroid rats from 8.1 ± 2.8 to 19.7 ± 5.0 kcal/day ( P < 0.001) but did not increase in the controls (8.7 ± 3.5 cf 9.4 ± 1.7 kcal/day; not significant). In conclusion, hyperthyroidism is associated with increased spontaneous physical activity and NEAT.

Our experiments were designed to determine the acute effects of 17β-estradiol on femoral veins from intact and ovariectomized female pigs. Rings of femoral veins with or without endothelium were suspended in organ chambers for measurement of isometric force. Concentration-response curves to 17β-estradiol (10−9to 10−5M) were obtained in veins contracted with prostaglandin F2αin the absence and presence of inhibitors of either estrogen receptors (ICI-182780; 10−5M), nitric oxide synthase [ NG-monomethyl-l-arginine (l-NMMA); 10−4M], soluble guanylate cyclase (1- H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10−5M), or potassium channels (tetraethylammonium; 10−2M). Estrogen receptors were identified with the use of Western blotting and immunostaining in veins of both groups. 17β-Estradiol caused acute endothelium-dependent relaxations in both groups. Relaxations to 17β-estradiol were inhibited byl-NMMA and 1- H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but not ICI-182780. Tetraethylammonium inhibited relaxations only in veins with endothelium from intact females. Results indicate that 17β-estradiol causes acute endothelium-dependent relaxations in femoral veins. The relative contribution of nitric oxide and K+channels as mechanisms involved in relaxations to 17β-estradiol in femoral veins is modulated by ovarian status.

Experiments were designed to determine how ovariectomy modulates mitogenic factors in platelets and how these factors affect proliferation of coronary arterial smooth muscle. Platelet-derived growth factors (PDGFABand PDGFBB), transforming growth factors (TGF-β1and TGF-β2), and vascular endothelial growth factor (VEGF165) were quantified in platelet lysates and platelet-poor plasma from adult gonadally intact and ovariectomized female pigs by ELISA. Proliferation of cultured coronary arterial smooth muscle cells (SMCs) from both groups of pigs was determined in response to autologous or heterologous platelet lysates. Platelet concentrations of PDGFBB, but not PDGFAB, TGF-β1, and TGF-β2, increased with ovariectomy. VEGF165was not detected in platelets from either group. Proliferation of SMCs from ovariectomized females was significantly greater on exposure to autologous or heterologous platelet lysates than proliferation of SMCs from intact females. These results indicate that ovariectomy increases concentrations of PDGFBBin platelets. Higher levels of PDGFBBin platelets in synergy with other platelet-derived products could contribute to increased proliferative arterial response to injury after ovariectomy.

This study evaluated the effects of serotonergic psychoactive agents on gastrointestinal functions in healthy human subjects. Participants received one of four regimens in a randomized, double-blind manner: buspirone, a 5-HT 1A receptor agonist (10 mg twice daily); paroxetine, a selective serotonin reuptake inhibitor (20 mg daily); venlafaxine-XR, a selective serotonin and norepinephrine reuptake inhibitor (75 mg daily); or placebo for 11 days. Physiological testing performed on days 8–11included scintigraphic assessment of gastrointestinal and colonic transit, the nutrient drink test, and assessment of the postprandial change in gastric volume. Fifty-one healthy adults (40 females, 11 males) participated in this study. No effects on gastric emptying or colonic transit were identified with any agent. Small bowel transit of a solid meal was accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and nausea scores. Venlafaxine-XR increased the postprandial change in gastric volume. Buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal functions in healthy humans. These data support the need for clinical and physiological studies of these agents in functional gastrointestinal disorders.