NAVIGATE 24-Month Results: Electromagnetic Navigation Bronchoscopy for Pulmonary Lesions at 37 Centers in Europe and the United States.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive, image-guided approach to access lung lesions for biopsy or localization for treatment. However, no studies have reported prospective 24-month follow-up from a large, multinational, generalizable cohort. This study evaluated ENB safety, diagnostic yield, and usage patterns in an unrestricted, real-world observational design. METHODS: The NAVIGATE single-arm, pragmatic cohort study (NCT02410837) enrolled subjects at 37 academic and community sites in seven countries with prospective 24-month follow-up. Subjects underwent ENB using the superDimension navigation system versions 6.3 to 7.1. The prespecified primary end point was procedure-related pneumothorax requiring intervention or hospitalization. RESULTS: A total of 1388 subjects were enrolled for lung lesion biopsy (1329; 95.7%), fiducial marker placement (272; 19.6%), dye marking (23; 1.7%), or lymph node biopsy (36; 2.6%). Concurrent endobronchial ultrasound-guided staging occurred in 456 subjects. General anesthesia (78.2% overall, 56.6% Europe, 81.4% United States), radial endobronchial ultrasound (50.6%, 4.0%, 57.4%), fluoroscopy (85.0%, 41.7%, 91.0%), and rapid on-site evaluation use (61.7%, 17.3%, 68.5%) differed between regions. Pneumothorax and bronchopulmonary hemorrhage occurred in 4.7% and 2.7% of subjects, respectively (3.2% [primary end point] and 1.7% requiring intervention or hospitalization). Respiratory failure occurred in 0.6%. The diagnostic yield was 67.8% (range: 61.9%-70.7%; 55.2% Europe, 69.8% United States). Sensitivity for malignancy was 62.6%. Lung cancer clinical stage was I to II in 64.7% (55.3% Europe, 65.8% United States). CONCLUSIONS: Despite a heterogeneous cohort and regional differences in procedural techniques, ENB demonstrates low complications and a 67.8% diagnostic yield while allowing biopsy, staging, fiducial placement, and dye marking in a single procedure.

Electromagnetic Navigation Bronchoscopy for Peripheral Pulmonary Lesions: One-Year Results of the Prospective, Multicenter NAVIGATE Study.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive technology that guides endoscopic tools to pulmonary lesions. ENB has been evaluated primarily in small, single-center studies; thus, the diagnostic yield in a generalizable setting is unknown. METHODS: NAVIGATE is a prospective, multicenter, cohort study that evaluated ENB using the superDimension navigation system (Medtronic, Minneapolis, Minnesota). In this United States cohort analysis, 1215 consecutive subjects were enrolled at 29 academic and community sites from April 2015 to August 2016. RESULTS: The median lesion size was 20.0 mm. Fluoroscopy was used in 91% of cases (lesions visible in 60%) and radial endobronchial ultrasound in 57%. The median ENB planning time was 5 minutes; the ENB-specific procedure time was 25 minutes. Among 1157 subjects undergoing ENB-guided biopsy, 94% (1092 of 1157) had navigation completed and tissue obtained. Follow-up was completed in 99% of subjects at 1 month and 80% at 12 months. The 12-month diagnostic yield was 73%. Pathology results of the ENB-aided tissue samples showed malignancy in 44% (484 of 1092). Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 69%, 100%, 100%, and 56%, respectively. ENB-related Common Terminology Criteria for Adverse Events grade 2 or higher pneumothoraces (requiring admission or chest tube placement) occurred in 2.9%. The ENB-related Common Terminology Criteria for Adverse Events grade 2 or higher bronchopulmonary hemorrhage and grade 4 or higher respiratory failure rates were 1.5% and 0.7%, respectively. CONCLUSIONS: NAVIGATE shows that an ENB-aided diagnosis can be obtained in approximately three-quarters of evaluable patients across a generalizable cohort based on prospective 12-month follow-up in a pragmatic setting with a low procedural complication rate.

The Evolutional History of Electromagnetic Navigation Bronchoscopy: State of the Art.

Electromagnetic navigation bronchoscopy (ENB) has come a long way from the early roots of electromagnetic theory. Current ENB devices have the potential to change the way lung cancer is detected and treated. This paper provides an overview of the history, current state, and future of ENB.

Electromagnetic navigation bronchoscopy to access lung lesions in 1,000 subjects: first results of the prospective, multicenter NAVIGATE study.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is an image-guided, minimally invasive approach that uses a flexible catheter to access pulmonary lesions. METHODS: NAVIGATE is a prospective, multicenter study of the superDimension™ navigation system. A prespecified 1-month interim analysis of the first 1,000 primary cohort subjects enrolled at 29 sites in the United States and Europe is described. Enrollment and 24-month follow-up are ongoing. RESULTS: ENB index procedures were conducted for lung lesion biopsy (n = 964), fiducial marker placement (n = 210), pleural dye marking (n = 17), and/or lymph node biopsy (n = 334; primarily endobronchial ultrasound-guided). Lesions were in the peripheral/middle lung thirds in 92.7%, 49.7% were <20 mm, and 48.4% had a bronchus sign. Radial EBUS was used in 54.3% (543/1,000 subjects) and general anesthesia in 79.7% (797/1,000). Among the 964 subjects (1,129 lesions) undergoing lung lesion biopsy, navigation was completed and tissue was obtained in 94.4% (910/964). Based on final pathology results, ENB-aided samples were read as malignant in 417/910 (45.8%) subjects and non-malignant in 372/910 (40.9%) subjects. An additional 121/910 (13.3%) were read as inconclusive. One-month follow-up in this interim analysis is not sufficient to calculate the true negative rate or diagnostic yield. Tissue adequacy for genetic testing was 80.0% (56 of 70 lesions sent for testing). The ENB-related pneumothorax rate was 4.9% (49/1,000) overall and 3.2% (32/1,000) CTCAE Grade ≥2 (primary endpoint). The ENB-related Grade ≥2 bronchopulmonary hemorrhage and Grade ≥4 respiratory failure rates were 1.0 and 0.6%, respectively. CONCLUSIONS: One-month results of the first 1,000 subjects enrolled demonstrate low adverse event rates in a generalizable population across diverse practice settings. Continued enrollment and follow-up are required to calculate the true negative rate and delineate the patient, lesion, and procedural factors contributing to diagnostic yield. TRIAL REGISTRATION: ClinicalTrials.gov NCT02410837 . Registered 31 March 2015.

Increased Post-procedural Non-gastrointestinal Adverse Events After Outpatient Colonoscopy in High-risk Patients.

BACKGROUND & AIMS: The incidence and predictors of non-gastrointestinal (GI) adverse events (AEs) after colonoscopy are not well-understood. We studied the effects of antithrombotic agents, cardiopulmonary comorbidities, and age on risk of non-GI AEs after colonoscopy. METHODS: We performed a retrospective longitudinal analysis to assess the diagnosis, procedure, and prescription drug codes in a United States commercial claims database (March 2010-March 2012). Data from patients at increased risk (n = 82,025; defined as patients with pulmonary comorbidities or cardiovascular disease requiring antithrombotic medications) were compared with data from 398,663 average-risk patients. In a 1:1 matched analysis, 51,932 patients at increased risk, examined by colonoscopy, were compared with 51,932 matched (on the basis of age, sex, and comorbidities) patients at increased risk who did not undergo colonoscopy. We tracked cardiac, pulmonary, and neurovascular events 1-30 days after colonoscopy. RESULTS: Thirty days after outpatient colonoscopy, non-GI AEs were significantly higher in patients taking antithrombotic medications (7.3%; odds ratio [OR], 10.75; 95% confidence interval, 10.13-11.42) or those with pulmonary comorbidities (1.8%; OR, 2.44; 95% confidence interval, 2.27-2.62) vs average-risk patients (0.7%) and in patients 60-69 years old (OR, 2.21; 95% confidence interval, 2.01-2.42) or 70 years or older (OR, 6.45; 95% confidence interval, 5.89-7.06), compared with patients younger than 50 years. The 30-day incidence of non-GI AEs in patients at increased risk who underwent colonoscopy was also significantly higher than in matched patients at increased risk who did not undergo colonoscopy in the anticoagulant group (OR, 2.31; 95% confidence interval, 2.01-2.65) and in the chronic obstructive pulmonary disease group (OR, 1.33; 95% confidence interval, 1.13-1.56). CONCLUSIONS: Increased number of comorbidities and older age (older than 60 years) are associated with increased risk of non-GI AEs after colonoscopy. These findings indicate the importance of determining comorbid risk and evaluating antithrombotic management before colonoscopy.

Design of a prospective, multicenter, global, cohort study of electromagnetic navigation bronchoscopy.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) procedures allow physicians to access peripheral lung lesions beyond the reach of conventional bronchoscopy. However, published research is primarily limited to small, single-center studies using previous-generation ENB software. The impact of user experience, patient factors, and lesion/procedural characteristics remains largely unexplored in a large, multicenter study. METHODS/DESIGN: NAVIGATE (Clinical Evaluation of superDimension™ Navigation System for Electromagnetic Navigation Bronchoscopy) is a prospective, multicenter, global, cohort study. The study aims to enroll up to 2,500 consecutive subjects presenting for evaluation of lung lesions utilizing the ENB procedure at up to 75 clinical sites in the United States, Europe, and Asia. Subjects will be assessed at baseline, at the time of procedure, and at 1, 12, and 24 months post-procedure. The pre-test probability of malignancy will be determined for peripheral lung nodules. Endpoints include procedure-related adverse events, including pneumothorax, bronchopulmonary hemorrhage, and respiratory failure, as well as quality of life, and subject satisfaction. Diagnostic yield and accuracy, repeat biopsy rate, tissue adequacy for genetic testing, and stage at diagnosis will be reported for biopsy procedures. Complementary technologies, such as fluoroscopy and endobronchial ultrasound, will be explored. Success rates of fiducial marker placement, dye marking, and lymph node biopsies will be captured when applicable. Subgroup analyses based on geography, demographics, investigator experience, and lesion and procedure characteristics are planned. DISCUSSION: Study enrollment began in April 2015. As of February 19, 2016, 500 subjects had been enrolled at 23 clinical sites with enrollment ongoing. NAVIGATE will be the largest prospective, multicenter clinical study on ENB procedures to date and will provide real-world experience data on the utility of the ENB procedure in a broad range of clinical scenarios. TRIAL REGISTRATION: ClinicalTrials.gov NCT02410837 . Registered 31 March 2015.

Navigational bronchoscopy at a community hospital: clinical and economic outcomes.

AIM: To evaluate the clinical and financial impact of introducing electromagnetic navigation bronchoscopy (ENB) at a community center. METHODS: This retrospective, single-arm, single-center study evaluated 90 consecutive patients who had undergone ENB in 2012. Radial probe endobronchial ultrasound was used to localize the lesion after initial ENB. ENB-aided diagnoses, follow-up procedures and treatments, and adverse events were collected through 2 years. RESULTS: ENB was conducted for lung biopsy (86 patients), fiducial placement (five), and/or dye marking (two). ENB-aided diagnostic yield was 82.6% (71/86), including 36 malignant and 35 nonmalignant cases. NSCLC was stage I-II in 84.6%. There were four false negatives. Sensitivity and negative predictive value were 90.0 and 88.6%. Pneumothorax occurred in 6/90 (5/6 with chest tube) and minor bleeding in four. The downstream revenue of new ENB cases was US$363,654. CONCLUSION: ENB introduction provided high diagnostic yield, early-stage diagnosis, acceptable safety, and was financially justified.

Boston Scientific Lotus valve.

As a result of recent randomised controlled trials and registry observations, transcatheter aortic valve replacement (TAVR) enjoys growing appeal for the treatment of patients at high or extreme risk from surgical aortic valve replacement. However, the current technologies and techniques have important limitations, including risk of stroke, vascular complications and paravalvular aortic regurgitation, which may in turn influence survival. While careful patient selection and screening may improve outcomes, new valve designs and iterations are required. The Lotus aortic valve replacement system is a new fully repositionable device designed to facilitate more precise delivery and minimise paravalvular regurgitation. The safety and efficacy of the Lotus valve are being studied systematically in the REPRISE clinical trial programme.

Bypass versus drug-eluting stents at three years in SYNTAX patients with diabetes mellitus or metabolic syndrome.

BACKGROUND: Diabetes mellitus increases adverse outcomes after coronary revascularization; however, the impact of metabolic syndrome is unclear. We examined the impact of diabetes and metabolic syndrome on coronary artery bypass graft surgery (CABG) and stenting outcomes to determine the optimal revascularization option for the treatment of complex coronary artery disease. METHODS: Patients (n = 1,800) with left main or three-vessel disease or both were randomly allocated to treatment with a TAXUS Express(2) paclitaxel-eluting stent (PES) or CABG, and were included in predefined nondiabetic (n = 1,348) or diabetic subgroups (n = 452); 258 patients with diabetes also had metabolic syndrome. RESULTS: Among diabetic patients, the 3-year major adverse cardiac and cerebrovascular event (MACCE) rate (22.9% CABG, 37.0% PES; p = 0.002) and revascularization rate (12.9% CABG, 28.0% PES; p < 0.001) were higher after PES treatment. Diabetes increased MACCE rates among PES-treated patients, but had little impact on results after CABG. Compared with CABG, PES treatment yielded comparable MACCE in diabetic patients (30.5% versus 29.8%, p =0.98) and nondiabetic patients (20.2% versus 20.3%, p =0.99) with low Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) study scores of 22 or less. For patients with SYNTAX Scores of 33 or greater, MACCE rates were lower with CABG (18.5% versus 45.9%, p < 0.001 diabetic; 19.8% versus 30.0%, p = 0.01 nondiabetic). Metabolic syndrome did not significantly predict MACCE or repeat revascularization. CONCLUSIONS: These exploratory analyses suggest that among diabetic patients with complex left main or three-vessel disease, or both, 3-year MACCE is higher after PES compared with CABG. Although PES is a potential treatment option in patients with less complex lesions, CABG should be the revascularization option of choice for patients with more complex anatomic disease, especially with concurrent diabetes. Metabolic syndrome had little impact on 3-year outcomes.

Paclitaxel-eluting stents compared with bare metal stents in diabetic patients with acute myocardial infarction: the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial.

BACKGROUND: In the prospective, randomized Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, implantation of paclitaxel-eluting stents (PES) safely reduced the rates of ischemic target lesion revascularization (TLR) compared with bare metal stents (BMS) in patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous intervention. Diabetes mellitus is a known predictor of adverse outcomes after percutaneous intervention in STEMI. We therefore sought to assess the impact of PES in diabetic patients with STEMI from the HORIZONS-AMI trial. METHODS AND RESULTS: A total of 478 patients with diabetes and 2527 without diabetes were randomly assigned to receive PES versus BMS. The 12-month rates of ischemic TLR were significantly reduced by PES compared with BMS in both diabetic (11.2% versus 5.2%; hazard ratio [95% confidence interval]=0.45 [0.21 to 0.93]; P=0.03) and nondiabetic (6.8% versus 4.3%, hazard ratio [95% confidence interval]=0.63 [0.44 to 0.92]; P=0.02) patients. In patients with insulin-treated diabetes, PES compared with BMS reduced the 12-month TLR rate from 21.4% to 7.3% (hazard ratio [95% confidence interval]=0.35 [0.12 to 1.03]; P=0.046). Angiographic late loss and binary restenosis at 13 months were also significantly reduced in PES-treated diabetic patients. There were no significant differences between the BMS and PES groups in the 12-month rates of death, reinfarction, stroke, or stent thrombosis in either diabetic or nondiabetic patients. CONCLUSIONS: In the large-scale, prospective, randomized HORIZONS-AMI trial, implantation of PES compared with BMS in patients with STEMI and diabetes mellitus resulted in significant reductions in ischemia-driven TLR and angiographic restenosis at 1 year, with comparable safety outcomes, including stent thrombosis. These results suggest that PES can safely be used to reduce restenosis in high-risk diabetic patients presenting with STEMI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Two-year results of paclitaxel-eluting stents in patients with medically treated diabetes mellitus from the TAXUS ARRIVE program.

Drug-eluting stents decrease revascularization compared with bare metal stents in diabetic patients, but few studies have compared drug-eluting stent use in diabetic versus nondiabetic patients. The objective of this study was to assess whether paclitaxel provides equivalent revascularization decrease in diabetic and nondiabetic patients. The ARRIVE registries enrolled 7,492 patients receiving TAXUS Express stents, including 2,112 with medically treated diabetes; results were compared with those in the remaining 5,380 nondiabetic patients. Two-year target lesion revascularization (TLR) was comparable in diabetic and nondiabetic patients (8.2% vs 7.7%, p = 0.59) and remained similar after multivariate adjustment for baseline differences (7.1% vs 6.8%, p = 0.41). There were no significant TLR differences between diabetic and nondiabetic patients with small vessels (9.7% vs 9.5%, p = 0.96) or left main coronary artery, 3-vessel, or bifurcation stenting (10.7% vs 13.1%, p = 0.41). Diabetes was not a significant TLR predictor (hazard ratio 0.92, 95% confidence interval 0.77 to 1.12, p = 0.41). Stent thrombosis (2.6% vs 2.4%, p = 0.55) and myocardial infarction (3.8% vs 3.0%, p = 0.09) rates were also similar for diabetic and nondiabetic patients. However, 2-year mortality was significantly increased in diabetic compared with nondiabetic patients (9.7% vs 5.3%, p <0.001). Increased mortality drove significantly increased major cardiac events in diabetics; however, there was no difference in stent-related major cardiac events (8.9% vs 10.1%, p = 0.13). In conclusion, these results suggest that TAXUS paclitaxel-eluting stents abrogate the increased diabetic risk of clinical restenosis previously reported with bare metal stents, with similar low risk of myocardial infarction or stent thrombosis for diabetic and nondiabetic patients. However, diabetic patients still have increased risk of 2-year mortality.

Questioning the living/nonliving dichotomy: evidence from a patient with an unusual semantic dissociation.

In this article the authors describe a patient (J.P.) whose category-specific naming deficit eluded the classical dichotomies between living versus nonliving items or visual versus functional attributes. At age 22, he had herpes simplex encephalitis followed by a left temporal lobectomy. J.P. was tested on measures of visual perception, category naming, fluency, and name-picture matching. He showed a severe impairment naming and identifying fruits, vegetables, and musical instruments. His performance with animals and birds was spared inconsistently, meaning that even the preserved categories were, at some point, affected. J.P.'s unusual deficit supports the hypothesis that semantic knowledge is organized in the brain on the basis of object properties, which can cut across the living-nonliving categorical distinction.

Identification and characterization of two novel low-molecular-weight dual specificity phosphatases.

We have cloned and characterized two novel human low molecular weight dual specificity phosphatases (LMW-DSPs). Both genes are expressed exclusively in the testis, but are not altered in any of several disease states examined. Transfection into COS cells indicates that both proteins are expressed in the nucleus and the cytoplasm. Both proteins are able to dephosphorylate the phosphotyrosine analog pNPP in vitro and can be inhibited by sodium orthovanadate. In vitro experiments also demonstrate that both DSPs can dephosphorylate single and diphosphorylated synthetic MAPK peptides, with preference for the phosphotyrosine and diphosphorylated forms over phosphothreonine. However, when co-transfected with MAPKs into COS cells, the novel DSPs exhibited no detectable in vivo activity against MAPKs under our conditions. Our data suggest that these novel LMW-DSPs might belong to a new subclass of testis-specific proteins that act independently of the MAPK signal transduction cascade and do not depend on N-terminal docking regions for substrate binding.