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.
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.
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.
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.
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.
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.
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).
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.
Background:
Fiducial markers (FMs) help direct stereotactic body radiation therapy (SBRT) and localization for surgical resection in lung cancer management. We report the safety, accuracy, and ...practice patterns of FM placement utilizing electromagnetic navigation bronchoscopy (ENB).
Methods:
NAVIGATE is a global, prospective, multicenter, observational cohort study of ENB using the superDimension™ navigation system. This prospectively collected subgroup analysis presents the patient demographics, procedural characteristics, and 1-month outcomes in patients undergoing ENB-guided FM placement. Follow up through 24 months is ongoing.
Results:
Two-hundred fifty-eight patients from 21 centers in the United States were included. General anesthesia was used in 68.2%. Lesion location was confirmed by radial endobronchial ultrasound in 34.5% of procedures. The median ENB procedure time was 31.0 min. Concurrent lung lesion biopsy was conducted in 82.6% (213/258) of patients. A mean of 2.2 ± 1.7 FMs (median 1.0 FMs) were placed per patient and 99.2% were accurately positioned based on subjective operator assessment. Follow-up imaging showed that 94.1% (239/254) of markers remained in place. The procedure-related pneumothorax rate was 5.4% (14/258) overall and 3.1% (8/258) grade ⩾ 2 based on the Common Terminology Criteria for Adverse Events scale. The procedure-related grade ⩾ 4 respiratory failure rate was 1.6% (4/258). There were no bronchopulmonary hemorrhages.
Conclusion:
ENB is an accurate and versatile tool to place FMs for SBRT and localization for surgical resection with low complication rates. The ability to perform a biopsy safely in the same procedure can also increase efficiency. The impact of practice pattern variations on therapeutic effectiveness requires further study.
Trial registration:
ClinicalTrials.gov identifier: NCT02410837.
Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.
To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis ...of sporadic CHD.
We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.
We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against ...COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M
), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M
In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one ...discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
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•A comprehensive proteogenomic analysis of 242 HGSOC tumors was performed•A lack of Chr17-LOH was observed to be associated with refractoriness•A 64-protein signature predicts refractoriness in multiple tumor cohorts•Pathway-based clustering reveals 5 subtypes validated in independent cohorts
Patients with high-grade serous ovarian cancers (HGSOCs) have a poor outcome, with the standard of care not having changed over the decades. A detailed characterization of the proteogenomic landscape of HGSOCs across multiple cohorts and validation studies identifies a distinct signature that predicts with high specificity a subset of patients with chemotherapy-refractory cancers and implicates potential therapeutic vulnerabilities.
The aim of this study was, first of all, to associate the mercury (Hg) concentrations and respiratory functions of the gold miners in the artisanal small-scale gold mining (ASGM) environment in San ...Martín de Loba, Colombia. We carried out a cross-sectional study using a survey whereby we collected basic demographic information, occupational medical history, and applied two validated questionnaires (Q16 and SF36). We measured Hg levels in all volunteers using direct thermal decomposition-atomic absorption spectrometry. Univariate and bivariate statistical analyses were carried out for all variables, performing logistic regression to assess the effect of ASGM on health outcomes. Volunteers enrolled (n = 124) were between the ages of 20 and 84 years (84% miners and 79% males). No changes were found in the systolic blood pressure, diastolic blood pressure, and heart rate from the ASGM miners, in crude and adjusted statistical analyses. ASGM miners increased 8.91 (95% confidence interval, 1.55-95.70) times the risk of having these than of having neurotoxic effects. Concentrations of total whole blood mercury (T-Hg) in all participants ranged from 0.6 to 82.5 with a median of 6.0 μg/L. Miners had higher T-Hg concentrations than non-miners (
-value = 0.011). Normal and abnormal respiratory spirometry patterns showed significant differences with the physical role and physical function of quality-of-life scales (the (
-value was 0.012 and 0.004, respectively). The spirometry test was carried out in 87 male miners, with 25% of these miners reporting abnormalities. Out of these, 73% presented a restrictive spirometry pattern, and 27%, an obstructive spirometry pattern. The ASGM population had higher Hg concentrations and worse neurotoxic symptomatology than non-miners of the same community.
The aim of the present study was to find if workers chronically exposed to lead (Pb) and cadmium (Cd) presented changes in their general health and in the clinical parameters of the population under ...study. We carried out a cross-sectional survey in a sample of informal workers in Cartagena, Colombia. The population under study was composed of male informal workers (≥18 years of age), with experience in their job, selected from occupational settings with potential exposure to Pb and Cd (i.e., mechanics, battery and garbage recyclers, and welders). The median age was 45 years (interquartile range (IQR), 33−53). The median blood Pb level (BLL) was 2 μg/dL (IQR, 0.76−6.22), and the median of blood Cd level (BCL) was 1.22 μg/L (IQR, 0.33−2.01). The study found that 33% of high exposure jobs with BLL > 5 μg/dL (n = 57), whereas in ‘control’ workers, this was 15.3% (n = 9). The highest BLLs were found in battery recyclers (82.1%; n = 23), followed by mechanics (37.3%, n = 22). In the logistic regression model adjusted by age, time on the job, smoking and elevated BCL and BLL increased 3.2 times (95% CI, 1.1−9.7) in mechanics and 29.6 times (95% CI, 7.2−145.6) in battery recyclers. This study found negative changes in the health of workers with higher chronic exposure to lead in Cartagena, Colombia.
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