Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism.

BACKGROUND: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). METHODS: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. RESULTS: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. CONCLUSIONS: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.

The Grand SANS FLUORO (SAy No Series to FLUOROsopy) Study: Examining Fluoroscopy Use in More than 1,000 Ablation Procedures.

The majority of electrophysiologists routinely use fluoroscopy (FLUORO) during ablation procedures for common arrhythmias despite the known complications of radiation exposure and protective lead use. This study assessed the safety of catheter ablation (CA) with FLUORO versus without FLUORO (SANS FLUORO) in patients with the following common arrhythmias: atrial fibrillation (AF), atrial flutter, supraventricular tachycardia, and ventricular tachycardia. A total of 1,258 CA procedures were performed in 816 consecutive patients over a 53-month period (SANS FLUORO CA: 609 patients; FLUORO CA: 209 patients). The secondary outcome was the efficacy of AF ablation in FLUORO versus SANS FLUORO patients. Ultimately, there was no statistically significant difference found concerning the safety of CA in the SANS FLUORO and FLUORO groups in terms of procedure time, vascular complications, tamponade, stroke, or death. FLUORO patients had markedly increased FLUORO time, increased radiation exposure, and increased dose-area product (all p < 0.0001). AF development after SANS FLUORO CA of AF was not different from that after FLUORO CA regardless of the pulmonary vein isolation (PVI) modality used (cryoablation versus radiofrequency) at 24 months (p = 0.21). Additionally, women fared just as well as men after CA ablation for AF. At 36 months, 58% of SANS FLUORO AF device patients were free from AF. As such, SANS FLUORO CA of common arrhythmias appears to be as safe as FLUORO CA but with a markedly reduced level of radiation exposure. Also, SANS FLUORO CA remains as effective as FLUORO CA in the prevention of AF for up to 24 months.

Clinical characteristics of children evaluated for suspected pulmonary embolism with D-dimer testing.

BACKGROUND: We sought to determine clinical variables in children tested for suspected pulmonary embolism (PE) that predict PE+ outcome for the development of paediatric PE prediction rule. METHODS: Data were collected by query of a laboratory database for D-dimer from January 2004 to December 2014 for a large multicentre hospital system and the radiology database for pulmonary vascular imaging in children aged 5-17. Using explicit, predefined methods, trained abstractors, determined if D-dimer was sent in the evaluation of PE and then recorded predictor data which was tested for association with PE+ outcome using univariate techniques. RESULTS: D-dimer was ordered in 526 children for clinical suspicion of PE. Thirty-four of 526 were PE+ (6.4%, 95% CI 4.3% to 8.7%). The radiology database identified 17 additional patients with PE (n=51 PE+ total). Children evaluated for PE were primarily in the ED setting (80%), teenagers (88%) and 2:1 female:male. Children with PE had higher mean heart and higher respiratory rate and a lower pulse oximetry and haemoglobin concentration. On univariate analysis, five conditions were more frequent in PE+ compared with no PE: surgery, central line, limb immobility, prior PE or deep vein thrombosis and cancer. CONCLUSIONS: The rate of PE diagnosis in children with D-dimer was 6.4%, similar to that seen in adults; most children with PE are over 13 years and had clinical predictors known to increase probability of PE in symptomatic adults. Future studies should use these criteria to develop a clinical decision rule for PE in children.

Diagnostic accuracy of the D-dimer in children.

BACKGROUND: We sought to measure the diagnostic accuracy of D-dimer in children with suspected pulmonary embolism (PE). METHODS: We queried our electronic medical record for quantitative D-dimer values obtained in all children ages 5-17 over 10 years in our 10-hospital system. Patients who had a D-dimer obtained in the evaluation of PE underwent supervised chart review to extract baseline demographics (age, sex, ethnicity), medical history, laboratory data and imaging results. PE was confirmed by imaging positive for deep vein thrombosis (DVT) or PE and excluded by imaging or no DVT or PE diagnosis within 90 days. RESULTS: Over a 10-year period, we identified 13 792 orders for D-dimer testing in 2554 unique patients. Chart review indicated that 526 (20.6%) unique patients had D-dimer testing performed in the evaluation of PE (Cohen's kappa=0.95, 95% CI 0.85 to 1.0). Most D-dimers (465/526, 88%) were ordered in children aged >12 years. Of these 526 children, 34 (6.4%, 95% CI) had a criterion standard positive for new or recurrent PE. The mean D-dimer value was 2104±1394 ng/mL in the 34/34 PE+ children and 586±962 ng/mL in PE- children with a sensitivity of 34/34 (100%, 89% to 100%) and a specificity of 290/492 (58%, 54% to 63%). The area under the receiver operating characteristic curve was 0.90 ((0.9)87-0.94). CONCLUSIONS: D-dimer is currently ordered in children for suspected PE in the emergency care setting, mostly in teenagers. The observed lower limit 95% CIs of 89% and 54% for diagnostic sensitivity and the specificity, respectively, suggest if used in patients with low-clinical probability, a normal D-dimer can safely exclude PE in children.

Evaluation of the pulmonary embolism rule out criteria (PERC rule) in children evaluated for suspected pulmonary embolism.

BACKGROUND: The pulmonary embolism rule out criteria (PERC) reliably predicts a low probability of PE in adults. We examine the diagnostic accuracy of the objective components of the PERC rule in children previously tested for PE. METHODS: Children aged 5-17 who had a D-dimer or pulmonary vascular imaging ordered from 2004 to 2014 in a large multicenter hospital network were identified by query of administrative databases. Using explicit, predefined methods, trained abstracters selected charts of children clearly tested for PE, collected the 8 objective variables for PERC, and determined PE criterion standard status (image or autopsy confirmed PE or deep vein thrombosis within 30 days by query of the Indiana Network for Patient Care (INPC)). RESULTS: We identified 543 patients, including 56 (10.3%, 95% CI: 7.8-13.1%) who were PE+, with a mean and median age of 15 years. All 8 objective criteria from PERC were negative in 170 patients (31%), including one with PE (false negative rate 0.6%, 0-3.2%). Diagnostic sensitivity and specificity were 98.2% (90.5-100%), and 34.7 (30.5-39.1%), respectively, leading to a likelihood ratio negative = 0.05 (0.1-0.27). When treated as a diagnostic test based upon sum of criteria positive, PERC had good discrimination between PE+ vs PE- with an area under receiver operating characteristic curve 0.81 (0.75-0.86). CONCLUSIONS: In this sample of children and teenagers with suspected PE, the PERC rule was negative in 31%, and demonstrated good overall diagnostic accuracy, including a low false negative rate. These data support the need for a large, prospective diagnostic validation study of PERC in children.

Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma.

Purpose: Squamous cell carcinoma of the anal canal (ASCC) accounts for 2% to 4% of gastrointestinal malignancies in the United States and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting.Experimental Design: We perform whole-exome sequencing of primary (n = 31) and recurrent (n = 30) ASCCs and correlate findings with clinical data. We compare genomic features of matched pre- and post-CRT tumors to identify genomic features of CRT response. Finally, we investigate the mutational underpinnings of an extraordinary ASCC response to immunotherapy.Results: We find that both primary and recurrent ASCC tumors harbor mutations in genes, such as PIK3CA and FBXW7, that are also mutated in other HPV-associated cancers. Overall mutational burden was not significantly different in pre- versus post-CRT tumors, and several examples of shared clonal driver mutations were identified. In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRAS or FBXW7). A patient with recurrent disease achieved an exceptional response to anti-programmed death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load.Conclusions: We perform comprehensive mutational analysis of ASCC and characterize mutational features associated with CRT. Although many primary and recurrent tumors share driver events, we identify several unique examples of clonal evolution in response to treatment. Clin Cancer Res; 23(12); 3214-22. ©2016 AACR.

MR imaging findings of acetabular dysplasia in adults.

OBJECTIVE: To evaluate the diagnostic accuracy of MR imaging in the identification of labral and articular cartilage lesions in patients with acetabular dysplasia. DESIGN AND PATIENTS: Pre-operative MR imaging was performed on 27 hips in 25 consecutive patients (16 males, 9 females, age range 19-52 years, mean age 31.2 years) with radiographic evidence of acetabular dysplasia (centre-edge angle of Wiberg <20 degrees). The average duration of symptoms was 16.2 months. Two musculoskeletal radiologists assessed MR images in consensus for the presence of abnormality involving the acetabular labrum and adjacent acetabular articular cartilage. A high resolution, non-arthrographic technique was used to assess the labrum and labral chondral transitional zone. Surgical correlation was obtained in all cases by a single surgeon experienced in hip arthroscopy and ten patients with normal hip MRI were included to provide a control group. RESULTS: The acetabular labra in the dysplastic hips demonstrated abnormal signal intensity, and had an elongated appearance when compared with the control group (mean length 10.9 mm vs 6.4 mm). Morphological appearances in the labra included surface irregularity, fissures and cleft formation. MR imaging correctly identified the severity of chondral abnormality in 24 of 27 hips (89%) when compared with arthroscopic findings. CONCLUSIONS: MR imaging demonstrates an elongated labrum, focal intra-substance signal change and irregularity and fissuring of the margins in patients with acetabular dysplasia. Abnormality is also identified at the labral chondral transitional zone, where fissuring, focal clefts, chondral deficiency and subchondral cyst formation may be apparent. A high-resolution, non-arthrographic technique can provide an accurate preoperative assessment and evaluate the presence of premature osteoarthritis.