Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy.

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and CYP2C19 polymorphisms.On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x109/L for clopidogrel and ticagrelor, respectively; p < .001) or following cessation of clopidogrel (7.23 (1.97) x109/L, at 6 months vs 7.56 (2.28) x109/L after treatment cessation; P < .001). This occurred independently of baseline biomarkers and CYP2C19 genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC.Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and CYP2C19 genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel's efficacy as well as therapeutic interaction with anti-inflammatory drugs.

Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease.

Background and Objective: Lung cancer is commonly associated with brain metastasis formation, and certain subtypes, such as anaplastic lymphoma kinase (ALK) rearranged disease, have an especially high propensity for early and frequent central nervous system (CNS) involvement for which treatment can be challenging. Historical management has centered on surgery and radiation therapy (RT), which persist as mainstays of treatment for large, symptomatic lesions and widespread CNS disease. To date, sustained disease control remains elusive, and the role for effective systemic adjunctive therapies is clear. Here we discuss the epidemiology, genomics, pathophysiology, identification, and management of lung cancer brain metastases with a particular emphasis on systemic treatment of ALK-positive disease according to the best available evidence. Methods: Review of PubMed and Google Scholar databases as well as ClinicalTrials.gov provided background and seminal trials for the local and systemic management of ALK rearranged lung cancer brain metastases. Key Content and Findings: The development of effective, CNS-penetrant systemic agents-including alectinib, brigatinib, ceritinib, and lorlatinib-has dramatically changed the management and prevention of ALK rearranged brain metastases. Most notably, there is a burgeoning role for upfront systemic therapy for both symptomatic and incidentally discovered lesions. Conclusions: Novel targeted therapies offer patients a pathway to delay, obviate, or supplement traditional local therapies while minimizing neurologic sequelae of treatment and may reduce the risk of brain metastasis formation. However, the selection of patients to whom local and targeted treatments is offered is not trivial, and the risks and benefits of both must be weighed carefully. More work is needed to establish treatment regimens that yield durable intra- and extracranial disease control.

Investigational treatment strategies in glioblastoma: progress made and barriers to success.

INTRODUCTION: Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005 comprises maximal safe resection followed by radiation with concurrent and adjuvant temozolomide; more recently, the addition of tumor treating fields was approved in the newly diagnosed and recurrent disease settings. AREAS COVERED: Searches of PubMed, Cochrane Library, and ClinicalTrials.gov provided a foundation for this review. We first describe early research including carmustine wafers, brachytherapy, anti-angiogenesis, and immune checkpoint inhibition for glioblastoma. Next, we discuss challenges precluding the translation of preclinical successes. This is followed by a description of promising treatments such as chimeric antigen receptor T-cell therapy as well as the recent qualified successes of cancer vaccinations. Non-immunotherapy trials are also highlighted, and ongoing or pending phase 2 and 3 clinical trials are codified in study tables. EXPERT OPINION: Unfortunately, hundreds of trials, including of agents effective in systemic malignancy, have not drastically changed management of glioblastoma. This may reflect unique resistance mechanisms and highlights a need for multimodality treatments beyond surgery, radiation, and conventional chemotherapy. Novel techniques, such as those in the emerging field of cancer neuroscience, may help uncover tolerable and effective regimens for this lethal malignancy.

Characterization of persistent atrial fibrillation with non-contact charge density mapping and relationship to voltage.

BACKGROUND: Despite studies using localized high density contact mapping and lower resolution panoramic approaches, the mechanisms that sustain human persistent atrial fibrillation (AF) remain unresolved. Voltage mapping is commonly employed as a surrogate of atrial substrate to guide ablation procedures. OBJECTIVE: To study the distribution and temporal stability of activation during persistent AF using a global non-contact charge density approach and compare the findings with bipolar contact mapping. METHODS: Patients undergoing either redo or de novo ablation for persistent AF underwent charge density and voltage mapping to guide the ablation procedure. Offline analysis was performed to measure the temporal stability of three specific charge density activation (CDA) patterns, and the degree of spatial overlap between CDA patterns and low voltage regions. RESULTS: CDA was observed in patient-specific locations that partially overlapped, comprising local rotational activity (18% of LA), local irregular activity (41% of LA), and focal activity (39% of LA). Local irregular activity had the highest temporal stability. LA voltage was similar in regions with and without CDA. CONCLUSION: In persistent AF, CDA patterns appear unrelated to low voltage areas but occur in varying locations with high temporal stability.

Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.

BACKGROUND: Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited. CASE SUMMARY: We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure. DISCUSSION: RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.

Outcome of Repair of Distal Radial and Ulnar Fractures in Dogs Weighing 4 kg or Less Using a 1.5-mm Locking Adaption Plate or 2.0-mm Limited Contact Dynamic Compression Plate.

Objectives Retrospective evaluation of repairing distal radial and ulnar fractures in small breed dogs with the Synthes 1.5-mm locking Adaption plate system and compare results in a similar group of patients repaired with the Synthes 2.0-mm limited contact-dynamic compression plate (LC-DCP). Methods Electronic medical records from one specialty referral centre were reviewed from March 21, 2010, to October 9, 2015, for patients weighing less than or equal to 4 kg that had a distal one-third radial and ulnar fracture repaired with a Synthes 1.5-mm locking adaption plate or Synthes 2.0-mm LC-DCP. Further inclusion criteria included application of the plate to the cranial surface of the radius via open reduction and internal fixation. Results Six 1.5-mm Adaption plates and 7 2.0-mm LC-DCPs were used to repair 13 distal radial and ulnar fractures in 12 dogs. There were three major complications in the 1.5-mm adaption plate group (one plate fracture, one screw pull-out and one fracture through a distal screw hole) and one major complication in the 2.0-mm LC-DCP group due to a re-fracture. All patients without a complication had good or excellent functional outcome. Clinical Significance The authors recommend that the 1.5-mm Adaption plate be used only when a 2.0-mm LC-DCP would not allow for a minimum of two screws in the distal segment and at the discretion of the surgeon.

Clinical benefits of incorporating doxycycline into a canine heartworm treatment protocol.

BACKGROUND: The objective of heartworm treatment is to improve the clinical condition of the patient and to eliminate pre-cardiac, juvenile, and adult worm stages with minimal complications. Pulmonary thromboembolisms are an inevitable consequence of worm death and can result in severe pulmonary reactions and even death of the patient. To minimize these reactions, various treatment protocols involving melarsomine, the only adulticidal drug approved by the US Food and Drug Administrations (FDA), in conjunction with macrocyclic lactone heartworm preventives and glucocorticosteroids have been advocated. The discovery of the bacterial endosymbiont Wolbachia in Dirofilaria immitis has led to several experimental studies examining the effects of administering doxycycline to reduce or eliminate Wolbachia organism. These studies have shown a decrease in gross and microscopic pathology of pulmonary parenchyma in experimental heartworm infections pretreated with doxycycline before melarsomine administration. METHODS: Electronic medical records from a large veterinary practice in northeast Alabama were searched to identify dogs treated for heartworms with melarsomine from January 2005 through December 2012. The search was refined further to select for dogs that met the following criteria: 1) received two or three doses of ivermectin heartworm preventive prior to melarsomine injections, 2) received one injection of melarsomine followed by two injections 4 to 8 weeks later, and 3) were treated with prednisone following melarsomine injections. The dogs were then divided into those that also were treated with doxycycline 10 mg/kg BID for 4 weeks (Group A, n = 47) and those that did not receive doxycycline (Group B, n = 47). The medical notes of all 94 cases were then reviewed for comments concerning coughing, dyspnea, or hemoptysis in the history, physical exam template, or from telephone conversations with clients the week following each visit. Any dog that died within one year of treatment from either cardiovascular or pulmonary problems was noted. RESULTS: Dogs from Group A receiving doxycycline had fewer respiratory complications (6.52%) and heartworm disease-related deaths (0%) than Group B (19.14% and 4.25%, respectively). CONCLUSIONS: Although there are not enough cases to indicate statistical significance, the results strongly suggest that including doxycycline into canine heartworm treatment protocols decreases post-treatment complications and mortality in naturally infected clinical cases.

Canine heartworms in coyotes in Illinois.

Canine heartworm (Dirofilaria immitis) disease affects wild canids and may be a factor impacting the health and population dynamics of coyotes (Canis latrans). Coyotes may serve also as a potential reservoir for transmission of these parasites to domestic dogs. We investigated 920 coyotes harvested by hunters and trappers throughout Illinois (USA) from 1995-1997. The objectives of the study were to: 1) survey the regional prevalence and intensity of heartworms in coyotes in Illinois, 2) determine whether heartworm intensity correlates with physical condition, particularly body weight and winter fat levels, and 3) evaluate the relationship between heartworm infections and the reproductive success of females. Prevalence of heartworms statewide was 16.0%. Prevalence was significantly higher in males (17.7%) than in females (14.1%; P = 0.04) and was higher in the older age-classes (P < 0.0001). The regional prevalence of heartworms increased from northern to southern Illinois. Intensity ranged from 1 to 111 with a mean of 8.7 (SD = 13.2) worms. Intensities did not differ significantly between sexes (P = 0.53) or among age-classes (P = 0.84). Most infected coyotes had low intensity infections, 78.2% carried < 12 heartworms, 11.6% had 12-24 worms, and 10.2% were infected with > 24 worms. Body weights were not correlated with the presence of heartworms, nor were levels of kidney fat and marrow fat. However, reproductive success was lower in infected females. The percent of yearling females that bred was lower among infected females, as was the number of offspring produced by adults > or = 3.5 yr old. Our study demonstrates that heavy infections adversely affect fur quality and reduce fecundity of some females, but these effects are small and few coyotes (4.1%) had enough worms to trigger them. Coyote populations have increased in Illinois during the past 20 yr, but prevalence and intensity of heartworm disease appears to have changed little in that period. We conclude that heartworm disease is only a minor factor influencing coyote population dynamics in Illinois.