George Leef

Molecular communication between tumor-associated fibroblasts and head and neck squamous cell carcinoma

Over the past few decades, it has become increasingly clear that the lethality of cancers depends on more than the malignant cells themselves. The environment those malignant cells are exposed to is just as important a determinant of their behavior. Head and neck squamous cell carcinoma (HNSCC) is both common and deadly. It is the 6th most frequently occurring cancers, and prognosis is still generally poor. Recent evidence indicates that activated fibroblasts residing within the tumor stroma play a significant role in promoting the aggressive spread often seen in head and neck cancer. Tumor associated fibroblasts (TAFs) have also been implicated in facilitating angiogenesis and suppressing the normal anti-tumor function of immune cells. Studying the signaling molecules involved in these processes will facilitate the development of promising targets and inhibitors to prevent tumor-associated fibroblasts from exerting their reinforcing effects on the tumor. In this article, we review the recent literature on the signals used in tumor associated fibroblast communication, with a focus on potential therapeutic targets. Further, we highlight the lead candidates for TAF-targeted therapeutic interventions. Future anti-cancer strategies may achieve better results than current approaches by targeting the support cells in tumor stroma in addition to the cancerous cells.

Gender differences in management and clinical outcomes of atrial fibrillation patients

BACKGROUND Prior research has identified gender differences in the epidemiology and clinical management of atrial fibrillation (AF). The primary aim of this study is to systematically analyze a cohort of AF men and women and evaluate their baseline demographics, treatment, and clinical outcomes by gender. METHODS We examined the records of 5976 (42% women) consecutive AF patients who were prescribed at least one anti-arrhythmic drug between 2006 and 2013. From this cohort, 4311 (72%) patients had anticoagulation data available and were included in the final analysis. Time to clinical events was assessed using survival analysis and adjusted for covariates using Cox regression. RESULTS Compared to men, women were older (73 years vs. 67 years, p<0.001), had higher CHADS2 scores (1.9 vs. 1.5, p<0.001), and fewer cardiac comorbidities. Compared to men, women were more often prescribed sotalol and less often dofetilide (p<0.001). Women were also less likely to be anticoagulated (76.8% vs. 82.5%, p<0.001). Over a mean follow-up of 40 months, women were more likely to die (HR 1.21, p=0.037) or to have an ischemic stroke (HR 1.35, p=0.058). Women also had higher rates of atrioventricular-nodal ablation (adjusted HR 2.11, p<0.001) and pacemaker implantation (adjusted HR 1.69, p<0.001) procedures, but lower rates of electrical cardioversions, AF ablations, and maze surgeries. CONCLUSIONS There are significant gender differences in baseline demographics and clinical outcomes of AF patients. Women have higher mortality and ischemic strokes and are less often prescribed anticoagulation therapy despite higher CHADS2 scores. These data have important clinical implications.

Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation

INTRODUCTION Although there are many different antiarrhythmic drugs (AADs) approved for rhythm management of atrial fibrillation (AF), little comparative effectiveness data exist to guide drug selection. METHODS We followed 5952 consecutive AF patients who were prescribed amiodarone (N=2266), dronedarone (N=488), dofetilide (N=539), sotalol (N=1718), or class 1C agents (N=941) to the primary end point of AF recurrence. RESULTS Median follow-up time was 18.2 months (range 0.1-101.6 months). Patients who were prescribed amiodarone had the highest, while patients on class 1C agents had the lowest baseline CHA2DS2-VASc score, Charlson comorbidity index, and burden of comorbid illnesses including coronary artery disease, congestive heart failure, diabetes mellitus, hyperlipidemia, chronic obstructive lung disease, chronic kidney disease, or cancer (p<0.05 for all comparisons). After adjusting for baseline characteristics, using dronedarone as benchmark, amiodarone [hazard ratio (HR) 0.58, p<0.001], class 1C agents (HR 0.70, p<0.001), and sotalol (HR 0.79, p=0.008), but not dofetilide (HR 0.87, p=0.178) were associated with less AF recurrence. In addition, compared to dronedarone, amiodarone and class 1C agents were associated with lower rates of admissions for AF (HR 0.55, p<0.001 for amiodarone; HR 0.71, p=0.021 for class 1C agents) and all-cause mortality was lowest in patients treated with class 1C agents (HR 0.42, p=0.018). The risk of stroke was similar among all groups. CONCLUSION Compared with dronedarone, amiodarone, class 1C agents, and sotalol are more effective for rhythm control, while dofetilide had similar efficacy. These findings have important implications for clinical practice.

Risk of Stroke and Death in Atrial Fibrillation by Type of Anticoagulation: A Propensity‐Matched Analysis

We examined the effect of novel oral anticoagulants (NOACs) compared to warfarin on the risk of death or stroke in atrial fibrillation (AF) patients in every day clinical practice.

Patient Outcomes According to Adherence to Treatment Guidelines for Rhythm Control of Atrial Fibrillation

Background Although guidelines for antiarrhythmic drug therapy in atrial fibrillation (AF) were published in 2006, it remains uncertain whether adherence to these guidelines affects patient outcomes. Methods and Results We retrospectively evaluated the records of 5976 consecutive AF patients who were prescribed at least 1 antiarrhythmic drug between 2006 and 2013. Patients with 1 or more prescribed antiarrhythmic drugs that did not comply with guideline recommendations comprised the non–guideline‐directed group (=2920); the remainder constituted the guideline‐directed group (=3056). Time to events was assessed using the survival analysis method and adjusted for covariates using Cox regression. Rates of adherence to the guidelines increased significantly with a higher degree of prescriber specialization in arrhythmias (49%, 55%, and 60% for primary care physicians, general cardiologists, and cardiac electrophysiologists, respectively, P=0.001) for the first prescribed antiarrhythmic drug. Compared to the non–guideline‐directed group, the guideline‐directed group had higher rates of heart failure, but lower baseline CHADS2‐VASc scores (P<0.001) and lower rates of coronary artery disease, valvular disease, hypertension, hyperlipidemia, pulmonary disease, and renal insufficiency (P<0.05 for all). During 45±26 months follow‐up, the guideline‐directed group had a lower risk of AF recurrence (hazard ratio=0.86, 95% CI=0.80 to 0.93), fewer hospital admissions for AF (hazard ratio=0.87, 95% CI=0.79 to 0.97), and fewer procedures for recurrent AF, including electrical cardioversion, pacemaker implantation, and atrioventricular nodal ablation (P<0.01 for all). The mortality and stroke risks were similar between the groups. Conclusions Adherence to published guidelines in the antiarrhythmic management of AF is associated with improved patient outcomes.

Independent mapping methods reveal rotational activation near pulmonary veins where atrial fibrillation terminates before pulmonary vein isolation

To investigate mechanisms by which atrial fibrillation (AF) may terminate during ablation near the pulmonary veins before the veins are isolated (PVI).

Mortality risk of long-term amiodarone therapy for atrial fibrillation patients without structural heart disease.

BACKGROUND Amiodarone is often prescribed in the management of atrial fibrillation (AF) but is known to cause significant end-organ toxicities. In this study, we examined the impact of amiodarone on all-cause mortality in AF patients with structurally normal hearts. METHODS We performed a retrospective cohort analysis of all AF patients with structurally normal hearts who were prescribed antiarrhythmic drugs (AAD) for rhythm control of AF at our institution from 2006 to 2013 (n = 2,077). Baseline differences between the amiodarone (AMIO: n = 403) and other AADs (NON-AMIO: n = 1,674) groups were corrected for using propensity score matching. RESULTS Amiodarone use as first-line therapy decreased significantly with a higher degree of prescriber specialization in arrhythmia management (31%, 22%, and 9% for primary care physicians, general cardiologists and cardiac electrophysiologists, respectively, p < 0.001). After propensity score matching, baseline comorbidities were balanced between the AMIO and NON-AMIO groups. Over a median follow-up of 28.2 months (range 6.0-100.9 months), amiodarone was associated with increased all-cause (HR 2.41, p = 0.012) and non-cardiac (HR 3.55, p = 0.008) mortality, but not cardiac mortality. AF recurrence and cardiac hospitalizations were similar between the two study groups. CONCLUSIONS Amiodarone treatment of AF is associated with increased mortality in patients without structural heart disease and therefore should be avoided or only used as a second-line therapy, when other AF therapies fail. Adherence to guideline recommendations in the management of AF patients impacts clinical outcome.

Safety and Efficacy of Rivaroxaban in Patients With Cardiac Implantable Electronic Devices: Observations From the ROCKET AF Trial

Background Although implantation of cardiac implantable electronic devices (CIEDs) in patients receiving warfarin is well studied, limited data are available on the use of oral factor Xa inhibitors in this setting. Methods and Results Using data from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (n=14 264), we compared baseline characteristics and clinical outcomes in patients with atrial fibrillation randomized to rivaroxaban versus warfarin who did and did not undergo CIED implantation or revision. In this post‐hoc, postrandomization, on‐treatment analysis, only the first intervention per patient was analyzed. During a median follow‐up of 2.2 years, 453 patients (242 rivaroxaban group; 211 warfarin group) underwent de novo CIED implantation (64.2%) or revision procedures (35.8%). Patients who received CIEDs were older, more likely to be male, and more likely to have past myocardial infarction, but had similar stroke risk compared to patients who did not receive CIEDs. Most patients who received a device had study drug interrupted for the procedure and did not receive bridging anticoagulation. During the 30‐day postprocedural period, 11 patients (4.55%) in the rivaroxaban group experienced bleeding complications compared with 15 (7.13%) in the warfarin group. Thromboembolic complications occurred in 3 patients (1.26%) in the rivaroxaban group and 1 (0.48%) in the warfarin group. Event rates were too low for formal hypothesis testing. Conclusions Bleeding and thromboembolic events were low in both rivaroxaban‐ and warfarin‐treated patients. Periprocedural use of oral factor Xa inhibitors in CIED implantation requires further study in prospective, randomized trials. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Large Morel-Lavallee lesion presenting as fungating mass with skin ulceration

A Morel-Lavallée lesion, a type of soft tissue degloving injury that has also been referred to as a chronic expanding hematoma, is a relatively rare condition that usually develops following traumatic injury. Here, we present a case of a 60-year-old male with a Morel-Lavallée lesion diagnosed over 5 years after a traumatic injury of the hip. He presented with a large fungating mass and overlying skin ulceration, which was highly suspicious for sarcoma. However, lack of other systemic findings and constitutional complaints, as well as negative imaging studies, did not support a diagnosis of malignancy. This information, combined with the history of remote trauma to the affected area, instead led us to suspect the alternative diagnosis of a Morel-Lavallée lesion. The diagnosis was later confirmed by pathology showing a chronic expanding hematoma. To our knowledge, a Morel-Lavallée lesion presenting as a fungating mass has not been previously described.

Geographic and racial representation and reported success rates of studies of catheter ablation for atrial fibrillation: Findings from the SMASH-AF meta-analysis study cohort

We performed a systematic review and meta‐analysis of geographic and racial representation and reported success rates of studies of catheter ablation for atrial fibrillation (AF).