Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Samples from Advanced Non-Small Cell Lung Cancer for Whole Genome, Whole Exome and Comprehensive Panel Sequencing.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from 220 EBUS-TBNA aspirates to evaluate their suitability for whole genome (WGS), whole exome (WES), and comprehensive panel sequencing. For a subset of 40 cases, the same nucleic acid extraction was sequenced using WGS, WES, and the TruSight Oncology 500 assay. Genomic features were compared between sequencing platforms and compared with those reported by clinical testing. A total of 204 aspirates (92.7%) had sufficient DNA (100 ng) for comprehensive panel sequencing, and 109 aspirates (49.5%) had sufficient material for WGS. Comprehensive sequencing platforms detected all seven clinically reported tier 1 actionable mutations, an additional three (7%) tier 1 mutations, six (15%) tier 2-3 mutations, and biomarkers of potential immunotherapy benefit (tumor mutation burden and microsatellite instability). As expected, WGS was more suited for the detection and discovery of emerging novel biomarkers of treatment response. WGS could be performed in half of all EBUS-TBNA aspirates, which points to the enormous potential of EBUS-TBNA as source material for large, well-curated discovery-based studies for novel and more effective predictors of treatment response. Comprehensive panel sequencing is possible in the vast majority of fresh EBUS-TBNA aspirates and enhances the detection of actionable mutations over current clinical testing.

Hallux Valgus, By Nature or Nurture? A Twin Study.

OBJECTIVE: To evaluate the contributions of shared but unmeasured genetic and environmental factors to hallux valgus (HV). METHODS: Between 2011 and 2012, 74 monozygotic (MZ) and 56 dizygotic (DZ) female twin pairs self-reported HV and putative risk factors, including footwear use across their lifespan. Estimates of casewise concordance (PC ), correlation (ρ), and odds ratios (ORs) were calculated, adjusting for age and other risk factors, and compared between MZ and DZ pairs using logistic regression, generalized estimating equations, and a maximum likelihood-based method, respectively. RESULTS: A total of 70 participants (27%) reported HV, with 12 MZ and 7 DZ pairs being concordant. After adjusting for age, twins were correlated (ρ = 0.27 [95% confidence interval (95% CI) 0.08, 0.46]) and concordant (PC = 0.45 [95% CI 0.29, 0.61]; mean age 58 years), with no difference between MZ and DZ pairs (P = 0.7). HV was associated with regularly wearing footwear with a constrictive toe-box during the fourth decade (adjusted OR 2.73 [95% CI 1.12, 6.67]). This risk factor was correlated in MZ (ρ = 0.38 [95% CI 0.15, 0.60]) but not DZ (ρ = -0.20 [95% CI -0.43, 0.03]) pairs. These correlations were significantly different (P = 0.002). CONCLUSION: Twins are correlated for HV, but we found no evidence that correlation was due to shared genetic factors. We identified an environmental risk factor, footwear with a constrictive toe-box, that is not shared to the same extent by MZ and DZ pairs, contrary to the assumption of the classic twin model. Footwear, and possibly genetic factors and unknown shared environmental factors, could contribute to developing HV.

Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health.

Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0 %; p < 0.001 in levetiracetam vs. -9.8 %; p < 0.001 in older AED group), FA (-1.46 %; p < 0.001 vs. -0.96 %; p < 0.001, respectively) and radial trabecular BMD (-1.46 %; p = 0.048 and -2.31 %; p = 0.013, respectively). C-terminal telopeptides of type I collagen (ßCTX; bone resorption marker) decreased in both groups (-16.1 %; p = 0.021 vs. -15.2 %; p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (-27.3 %; p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover.

The effects of smoking on bone health.

Osteoporotic fractures are a major public health problem in most developed countries and an increasing concern in much of the developing world. This healthcare burden will increase significantly worldwide over the next 20 years due to aging of the population. Smoking is a key lifestyle risk factor for bone loss and fractures that appears to be independent of other risk factors for fracture such as age, weight, sex and menopausal status. This review discusses the effects of smoking on bone health in pre-menopausal and post-menopausal women and men. Data from twin studies and the three main published meta-analyses are presented. Possible mechanisms by which smoking affects bone mass are reviewed. Despite smoking being a major lifestyle risk factor for osteoporosis, the mechanisms underlying smoking-associated bone loss and fracture risk remain poorly understood. The effect appears dose-dependent, and may be, at least partially, reversible. However, more work is required to confirm and characterize the reversibility of smoking-associated bone defects. Finally, strategies for quitting smoking are discussed. Encouragement of lifestyle alterations, including smoking cessation, should be a major component of any bone therapeutic programme.