Citations

There are no evidence-based guidelines for antithrombotic therapy in left ventricular assist device patients. We evaluated the efficacy of a multi-agent, test-guided protocol, which remained consistent throughout our use of the Heartware HVAD. Thrombelastography and platelet function analyzer (PFA)-100 guide antiplatelet titration. Goals are normal kaolin thrombelastography maximum amplitude and prolonged PFA-100. We analyzed incidence and rates of nonprocedural bleeding, stroke, and pump thrombosis for all 81 primary Heartware left ventricular assist devices implanted since 2011. For each event, we examined whether each test was within goal range. We also compared medication burden and dosage between patients with and without events. Pump thrombosis and hemorrhagic stroke each occurred in two patients (2.5%; 0.03 events/patient-year [EPPY]), and ischemic stroke in six (7.4%; 0.10 EPPY). Nonprocedural bleeding occurred 75 times in 34 patients (42%; 1.24 EPPY), primarily gastrointestinal (28%; 0.66 EPPY). Subtherapeutic international normalized ratio (INR) was the most common at thrombotic events; supratherapeutic partial thromboplastin time, international normalized ratio (INR), and PFA-adenosine diphosphate (ADP) were common at bleeding events. Medication burden and dosage were lower in patients with events than in stable patients. Protocol-guided antithrombotic therapy resulted in low rates of pump thrombosis and hemorrhagic stroke. Ischemic stroke and gastrointestinal bleeding rates were higher than in a comparable HVAD population. Optimization of our protocol to decrease its complexity and to reduce bleeding is underway.

Abstract Background New treatment strategies for metastatic breast cancer (mBC) are mainly driven by therapies against specific targets. BRCA mutations are one of the few established actionable targets, with PARP-Inhibitors and Platinum showing high efficacy in mBC. Hereditary cancer testing panels are now broadly used for identification of individuals with BRCA1/2 mutations who may benefit from these therapies. Many of these panels also contain other predisposition genes involved in BRCA-related DNA repair pathways, but the clinical relevance of mutations in these genes remain unclear. The aim of this study was to describe the mutation rates of BRCA1/2 and panel-based predisposition genes, and the associated clinical characteristics of individuals with these mutations, in a prospective cohort of mBC patients. Methods The PRAEGNANT mBC registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with a focus on molecular biomarkers. Patients receiving any therapeutic regimen are eligible for this registry. Germline DNA was collected at study entry and genotyped for 37 cancer predisposition genes including BRCA1 and BRCA2. The frequency of mutations in each gene was determined, and associations between mutations and patient and tumor characteristics, metastatic pattern, and overall survival were assessed. Results Mutations in established high (odds ratio (OR)>5.0) and moderate risk (OR>2.0) breast cancer genes (BRCA1/2, PALB2, CHEK2, ATM, RAD51D, BARD1, and MSH6) were seen in 123 of 1462 tested patients with mBC (8.4%). BRCA1 and BRCA2 mutations were seen in 1.4% and 2.9% of patients respectively. Most frequently mutated non-BRCA panel genes were CHEK2, PALB2 and ATM with 2.8%, 0.8% and 0.6% of patients. Mutation frequency varied with regard to patients who developed brain metastases, visceral metastases or bone only metastases. BRCA1 or BRCA2 mutations were seen frequently in patients with brain (5.3%) or visceral metastases (5.2%), but were present in only 2.5% patients with bone only metastases and 1.5% of patients with lesions in other locations. Panel genes were equally distributed among all metastatic patients. PALB2 mutations (n=11) were only seen in patients with brain (1.9%) and visceral metastases (0.9%), but not in patients with bone metastases or other locations. 36.4% (N=4) of all patients with PALB2 mutations developing a brain metastasis. When adjusted for other mBC prognostic factors, a mutation (all genes) was associated with an unfavorable prognosis (HR: 1.50; 95%CI: 1.04 to 2.30, p=0.03). Mutation frequencies were similar according to therapy lines. All other associations with molecular subtypes and risk factors were similar to primary breast cancer cases. Conclusion Mutations in high and moderate risk breast cancer genes were frequent in metastatic breast cancer patients. The frequency was substantially higher than the 4 to 5% mutation frequency observed among unselected primary breast cancer patients, but is consistent with recent results from studies of metastatic prostate cancer patients. Patients with brain and visceral metastases had the highest BRCA mutation rates. Results suggested that PALB2 mutations may be more frequent in patients with brain metastases. Citation Format: Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, Lilyquist J, Hartkopf AD, Taran FA, Janni W, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Untch M, Kolberg H-C, Fehm TN, Overkamp F, Wallwiener D, Brucker SY, Schneeweiss A, Couch F. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-02.

Objective A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. Design Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. Results We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. Conclusion Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

AbstractThe relationship between clinicopathologic diagnosis and 123I‐FP‐CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal 123I‐FP‐CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non‐Lewy body disease cases (P = 0.002). In this study, abnormal 123I‐FP‐CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of 123I‐FP‐CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

AbstractObjectivesThe objective was to develop a patient decision aid (DA) to promote shared decision making (SDM) for stable, alert patients who present to the emergency department (ED) with syncope.MethodsUsing input from patients, clinicians, and experts in the field of syncope, health care design, and SDM, we created a prototype of a paper‐based DA to engage patients in the disposition decision (admission vs. discharge) after an unremarkable ED evaluation for syncope. In phase 1, we conducted one‐on‐one semistructured exploratory interviews with 10 emergency physicians and 10 ED syncope patients. In phase 2, we conducted one‐on‐one directed interviews with 15 emergency care clinicians, five cardiologists, and 12 ED syncope patients to get detailed feedback on DA content and design. We iteratively modified the aid using feedback from each interviewee until clarity and usability had been optimized.ResultsThe 11 × 17‐inch, paper‐based DA, titled SynDA, includes four sections: 1) explanation of syncope, 2) explanation of future risks, 3) personalized 30‐day risk estimate, and 4) disposition options. The personalized risk estimate is calculated using a recently published syncope risk‐stratification tool. This risk estimate is stated in natural frequency and graphically displayed using a 100‐person color‐coded pictogram. Patient‐oriented questions are included to stimulate dialogue between patient and clinician. At the end of the development process, patient and physician participants expressed satisfaction with the clarity and usability of the DA.ConclusionsWe iteratively developed an evidence‐based DA to facilitate SDM for alert syncope patients after an unremarkable ED evaluation. Further testing is required to determine its effects on patient care. This DA has the potential to improve care for syncope patients and promote patient‐centered care in emergency medicine.

Endothelin-1 (ET-1) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P < 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF.

The present study used real-time confocal microscopy to examine the effects of the β2-adrenoceptor agonist salbutamol on regulation of intracellular Ca2+concentration ([Ca2+]i) in myotubes derived from neonatal mouse limb muscles. Immunocytochemical staining for ryanodine receptors and skeletal muscle myosin confirmed the presence of sarcomeres. The myotubes displayed both spontaneous and ACh-induced rapid (<2-ms rise time) [Ca2+]itransients. The [Ca2+]itransients were frequency modulated by both low and high concentrations of salbutamol. Exposure to α-bungarotoxin and tetrodotoxin inhibited ACh-induced [Ca2+]itransients and the response to low concentrations of salbutamol but not the response to higher concentrations. Preexposure to caffeine inhibited the subsequent [Ca2+]iresponse to lower concentrations of salbutamol and significantly blunted the response to higher concentrations. Preexposure to salbutamol diminished the [Ca2+]iresponse to caffeine. Inhibition of dihydropyridine-sensitive Ca2+channels with nifedipine or PN-200-110 did not prevent [Ca2+]ielevations induced by higher concentrations of salbutamol. The effects of salbutamol were mimicked by the membrane-permeant analog dibutyryl adenosine 3′,5′-cyclic monophosphate. These data indicate that salbutamol effects in skeletal muscle predominantly involve enhanced sarcoplasmic reticulum Ca2+release.

We measured antral volumes and propulsion-retropulsion for individual peristaltic cycles using the dynamic spatial reconstructor in three female mongrel dogs. Our aim was to quantify the effect of intestinal perfusion of equicaloric, isotonic, and isomolar nutrients (maltose, 32.5 mg/100 ml; casein hydrolysate, 32.5 mg/100 ml; and oleic acid 15.5 mg/100 ml) at a rate of 10 ml/min in the upper small intestine on total antral volume and the propulsion-retropulsion function of the "antral pump." Isotonic saline was used as a control solution. Isotonic gastrografin (600 ml) was instilled intragastrically as a meal. A 6-channel perfused manometric assembly was used to record antral phasic pressure activity. Antral volume was significantly lower (P < 0.05) in response to fat perfusion compared with other nutrients or isotonic saline. The propulsion-retropulsion ratio was also significantly reduced (P < 0.05) in response to fat perfusion in the upper small intestine. Our study, therefore, indicates that the fraction of a liquid meal delivered to the antrum is determined, at least in part, by the upper small intestinal nutrients and also that the presence of fat in the small intestine alters the propulsion-retropulsion function of the antrum.