Nurse-Delivered Brief Behavioral Treatment for Insomnia in Lung Cancer Survivors: A Pilot RCT.

Objective/Background: Insomnia occurs in 50 to 80% of lung cancer survivors. Cognitive behavioral therapy is the standard treatment for insomnia (CBTI); however, treatment length and lack of psychologists trained in CBTI limits access. Brief Behavioral Treatment for Insomnia (BBTI), a nurse-delivered modified CBTI, is proposed. This feasibility pilot study sought to compare the BBTI intervention to attention control Healthy Eating Program (HEP) for insomnia in lung cancer survivors. Participants: The participants comprised adults, 21 years of age or older with insomnia and stage I/II non-small cell lung cancer, more than 6 weeks from surgery and living in Western NY. Methods: Participants (n = 40) were randomly assigned to an experimental (BBTI) or attention control condition (Healthy Eating Program). Thirty participants completed the study. Results: Participants were 66 years of age (± 7.6; range 53-82), 40% (n = 16) male, 87.5% (n = 35) Caucasian, 50% (n = 20) married, BMI 27.7 (± 5.8), and 12% (n = 5) never smokers. Baseline sleep diary sleep efficiency, ISI and other baseline covariates were balanced between the groups. Sleep efficiency improved ≥85% in BBTI group (p = .02), but not in HEP control group (p = 1.00). Mean ISI for BBTI and attention control were 6.40 ± 4.98 and 14.10 ± 4.48 (p = .001) respectively. In addition, BBTI group mean total FACT-L score improved by 6.66 points from baseline while HEP group score worsened (p = .049). Conclusions: BBTI is a practical, evidence-based, clinically relevant intervention that improved sleep and quality of life in lung cancer survivors with insomnia. Additional research to evaluate efficacy, duration, and implementation strategies are essential.

Lower airway bacterial microbiome may influence recurrence after resection of early-stage non-small cell lung cancer.

OBJECTIVE: The lower airway bacterial microbiome influences carcinogenesis and response to immunotherapy in non-small cell lung cancer (NSCLC). We investigated the association of this microbiome with recurrence in early NSCLC. METHODS: Microbiomes of presurgery bronchoalveolar lavage (BAL) and saliva, and resected stage I NSCLC tumor and adjacent lung tissues of 48 patients were examined by 16S gene sequencing. Tumor gene expression was measured by RNA sequencing. RESULTS: Spatial relationships of the different biospecimen types was reflected in their microbiomes, with microbiomes of BAL intermediate to those of saliva and lung tissue. BAL and saliva microbiomes were less dissimilar in patients with high α-amylase levels in BAL, indicating oral aspiration as a source of lower airway microbiota. BAL microbiomes of patients with recurrence within 32 months of surgery differed from those without recurrence during ≥32 months of follow-up (n = 18 each), despite no difference for age, sex, smoking history, and tumor histology and grade. The recurrence-associated BAL microbiome signature was present in 16 of the 18 recurrence cases but in only two of the others. Signature presence was associated with shorter recurrence-free survival (log-rank test P < .001; hazard ratio = 14.5), and greater expression in tumors of genes for cell proliferation and epithelial mesenchymal transition. Immune cellular composition of the tumor microenvironment was not different between patients with and without the signature. CONCLUSIONS: Presurgery composition of lower airway microbiome may be associated with recurrence of early NSCLC. This association may reflect an influence of the microbiome on tumor biology.

Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions.

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.

Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression.

Purpose: Lung cancer is the leading cause of cancer-related death in the United States. The molecular events preceding the onset of disease are poorly understood, and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with lung cancer. Here, we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in lung cancer chemoprevention.Experimental Design: Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with (n = 50) and without (n = 25) PMLs. Using surrogate variable and gene set enrichment analysis, we identified genes, pathways, and lung cancer-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker.Results: We identified 280 genes in the airway field associated with the presence of PMLs. Among the upregulated genes, oxidative phosphorylation was strongly enriched, and IHC and bioenergetics studies confirmed pathway findings in PMLs. The relationship between PMLs and squamous cell carcinomas (SCC) was also confirmed using published lung cancer datasets. The biomarker performed well predicting the presence of PMLs (AUC = 0.92, n = 17), and changes in the biomarker score associated with progression/stability versus regression of PMLs (AUC = 0.75, n = 51).Conclusions: Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high risk for PML progression and monitor outcome in chemoprevention trials. Clin Cancer Res; 23(17); 5091-100. ©2017 AACR.

Endobronchial Ultrasound Bronchoscope Damage.

Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration is an effective, safe, and cost-effective diagnostic bronchoscopy technique for the work-up of mediastinal lymphadenopathy. Concern has been raised, however, about the high cost of convex-probe EBUS bronchoscope repairs. The damage is usually due to breakage of the insertion tube (the flexible part that is advanced into the airways), moisture invasion and damages to the working channel, image guide bundle, or umbilical cord. Understanding the root cause of EBUS scope damage is important for its prevention. We describe 2 unusual cases of EBUS scope damage. In the first case, the distal black rubber covering of the EBUS scope insertion tube was damaged due to friction with the edge of an endotracheal tube and in the second case, the EBUS scope insertion tube was angulating laterally instead of vertically during the flexion maneuver, probably due to scope manipulation while wedged tightly in a segmental bronchus.

Reporting of central airway obstruction on radiology reports and impact on bronchoscopic airway interventions and patient outcomes.

BACKGROUND: Central airway obstruction (CAO) is a serious condition that affects patients with both benign and malignant diseases. Timely recognition of CAO is crucial for prompt intervention aimed at improving the symptoms and quality of life of these patients. The aim of this study is to evaluate the formal radiology reporting of CAO and its impact on patients' outcomes. METHODS: The medical records of patients who underwent advanced therapeutic bronchoscopy for CAO from August 2013 to September 2014 were retrospectively reviewed. Three researchers each reviewed 14 of the 42 formal radiology reports that were performed at 16 different medical and radiology centers.Patient characteristics were reported as means, medians, and standard deviations for continuous variables, and as frequencies and relative frequencies for categorical variables. RESULTS: Out of 42 patients who underwent advanced bronchoscopy for planned therapeutic intervention, only 30 had radiology and pulmonology concordance about the airway findings of CAO. This is an agreement rate of 71.4% [95% confidence interval (CI): 56.7-83.3%] or a disagreement rate of 28.6% (95% CI: 16.7-43.3%). The radiology reports did not mention 31% of CAO on CT scans. The median time from CT imaging to bronchoscopy was significantly longer in patients with CAO not reported by the radiologists (21 versus 10 days; p = 0.011). Most patients improved postoperatively with no significant difference between the two groups. CONCLUSIONS: Findings of CAOs were not described in a significant proportion of radiology reports. This results in significant delay in bronchoscopic airway management.

Aspirin use and the risk of bleeding complications after therapeutic bronchoscopy.

BACKGROUND: Aspirin use has been shown to be safe for patients undergoing certain diagnostic bronchoscopy procedures such as transbronchial biopsies and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration. However, there are no studies documenting the safety of aspirin in patients undergoing therapeutic bronchoscopy. The aim of this study is to evaluate whether aspirin increases the risk of bleeding following therapeutic bronchoscopy. METHODS: This was a retrospective study to determine if there was a higher risk of bleeding in patients on aspirin undergoing therapeutic bronchoscopy compared with those not on aspirin. Patient characteristics were reported by cohort using the mean, median, and standard deviation for continuous variables, and using frequencies and relative frequencies for categorical variables. RESULTS: Of the 108 patients who had multimodality therapeutic bronchoscopy, 17 (15.7%) were taking aspirin and 91 (84.3%) were not on aspirin. Patients in the aspirin group were older than those in the no aspirin group (median age: 66 versus 60 years, p = 0.007). The treatment modalities were similar in both groups except that more patients in the no aspirin group were treated with argon plasma coagulation (APC) compared to the aspirin group (60.4% versus 29.4%, p = 0.031). The estimated blood loss (EBL) between the aspirin and no aspirin groups was not significantly different (mean: 6.0 versus 6.7 ml; median: 5.0 versus 5.0, p = 0.36). Overall, there was no difference in complications between both groups. CONCLUSION: Aspirin use was not associated with increased risk of bleeding or procedure-related complications after therapeutic bronchoscopy.

The Case for a Pre-Cancer Genome Atlas (PCGA).

Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a "Pre-Cancer Genome Atlas (PCGA)," a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding "field of injury" collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative "big-data" effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention.

Vitamin D3 intake modulates diaphragm but not peripheral muscle force in young mice.

Recent data support an important role for vitamin D in respiratory health. We tested the hypothesis that dietary vitamin D3 (VD3) intake modulates diaphragm (DIA) strength. Four-week-old female A/J mice (n = 10/group) were randomized to receive diets containing 100 IU VD3/kg (low), 1,000 IU VD3/kg (reference), or 10,000 IU VD3/kg (pharmacologic). After 6 wk of dietary intervention, plasma 25-hydroxyvitamin D3 (25D3) levels, DIA and extensor digitorum longus (EDL) in vitro contractile properties, and fiber cross-sectional area (CSA) were measured. Myosin heavy chain (MHC) composition and Akt/Foxo3A growth signaling were studied in the DIA and tibialis anterior. Mice fed the low, reference, and pharmacologic diets had average 25D3 levels of 7, 21, and 59 ng/ml, respectively. Maximal DIA force, twitch force, and fiber CSA were reduced 26%, 28%, and 10% (P < 0.01), respectively, in mice receiving the low-VD3 diet compared with the reference and pharmacologic diets. EDL force parameters were unaltered by diet. Effects of VD3 intake on DIA force were not observed in mice that began dietary intervention at 12 wk of age. VD3 intake did not alter the MHC composition of the DIA, indicating that decreases in force and CSA in young mice were not due to a switch in fiber type. Paradoxically, low VD3 intake was associated with activation of anabolic signaling in muscle (hyperphosphorylation of Akt and Foxo3A and decreased expression of autophagy marker LC3). These studies identify a potential role of dietary VD3 in regulating DIA development and insulin sensitivity.

Neutrophils, nitric oxide, and microvascular permeability in severe sepsis.

STUDY OBJECTIVES: Alterations in microvascular permeability are prevalent in patients with sepsis; a recent study reported that patients with septic shock had increased capillary filtration coefficient (Kf), a noninvasive index of microvascular permeability. We aimed to determine whether patients with severe sepsis had increased Kf, and whether the magnitude of Kf correlated with indexes of nitric oxide activity and neutrophil activation. DESIGN: Single-center, prospective study. SETTING: Twenty-five-bed ICU of a medical college-affiliated teaching hospital. PATIENTS: Fifteen ICU patients with severe sepsis based on the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria of 1992, and 10 nonseptic ICU patients as control subjects. INTERVENTIONS: Kf was measured by venous congestion plethysmography, plasma nitrate/nitrite (NOx) by chemiluminescence, and neutrophil expression of alpha4-integrin (an index of neutrophil activation) by flow cytometry. MEASUREMENTS AND RESULTS: Septic patients had higher Kf than nonseptic control subjects. Kf of septic patients was 5.6 +/- 0.6 x 10(-3) mL.min(-1).100 mL tissue(-1).mm Hg(-1) (mean +/- SEM, mL.min(-1).100 mL tissue(-1).mm Hg(-1) = Kf units [KfU]) as compared to 3.9 +/- 0.5 x 10(-3) KfU in nonseptic ICU patients (p < 0.05). There was no correlation between plasma NOx and Kf, or between neutrophil alpha4-integrin expression and Kf in patients with sepsis. Septic patients with clinical evidence of edema had significantly higher Kf (p < 0.05) than nonedematous septic patients. CONCLUSIONS: ICU patients with severe sepsis have increased Kf, a noninvasive index of microvascular water permeability. The magnitude of hyperpermeability did not correlate with NOx levels or one index of neutrophil activation (alpha4-integrin expression). Presence of peripheral edema in these patients was associated with increased Kf, and may represent a simple, clinical indicator of altered microvascular permeability in sepsis.

Black Endobronchial Ultrasound.

The infrequent bronchoscopic finding of black airway pigmentation due to a variety of causes has been labeled as "Black Bronchoscopy." Black bronchioalveolar lavage has been sometimes described in tobacco, marijuana, and crack cocaine smokers. To add to this interesting panorama of bronchoscopic findings, we describe cases of black endobronchial ultrasound-guided transbronchial needle aspirates due to metastatic melanoma and anthracotic lymph nodes.

Neurosarcoidosis presenting as status epilepticus: a new bronchoscopic complication.

Flexible bronchoscopy is considered a relatively safe procedure. Neurological complications related to bronchoscopy are extremely rare. We report a patient with granulomatous panuveitis due to suspected sarcoidosis manifesting as altered mental status and status epilepticus after an elective diagnostic bronchoscopy. Cerebrospinal fluid and magnetic resonance imaging findings confirmed diffuse leptomeningeal inflammation suggesting neurosarcoidosis. The patient was successfully treated with corticosteroids with complete resolution of central nervous system findings. To the best of our knowledge, this complication has not been reported before in any sarcoidosis patient undergoing bronchoscopy.

Substernal thyroid biopsy using Endobronchial Ultrasound-guided Transbronchial Needle Aspiration.

Substernal thyroid goiter (STG) represents about 5.8% of all mediastinal lesions(1). There is a wide variation in the published incidence rates due to the lack of a standardized definition for STG. Biopsy is often required to differentiate benign from malignant lesions. Unlike cervical thyroid, the overlying sternum precludes ultrasound-guided percutaneous fine needle aspiration of STG. Consequently, surgical mediastinoscopy is performed in the majority of cases, causing significant procedure related morbidity and cost to healthcare. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) is a frequently used procedure for diagnosis and staging of non-small cell lung cancer (NSCLC). Minimally invasive needle biopsy for lesions adjacent to the airways can be performed under real-time ultrasound guidance using EBUS. Its safety and efficacy is well established with over 90% sensitivity and specificity. The ability to perform EBUS as an outpatient procedure with same-day discharges offers distinct morbidity and financial advantages over surgery. As physicians performing EBUS gained procedural expertise, they have attempted to diversify its role in the diagnosis of non-lymph node thoracic pathologies. We propose here a role for EBUS-TBNA in the diagnosis of substernal thyroid lesions, along with a step-by-step protocol for the procedure.

Needle assembly malfunction: an unusual complication related to endobronchial ultrasound-guided transbronchial needle aspiration.

Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration has become an invaluable tool for thoracic physicians. Along with medical complications, it is also important to understand the equipment-related malfunctions. The EBUS scope is delicate and requires dedicated needle assembly for performing the needle aspirates. EBUS scope damage could be expensive and has been well described. We report 2 rare cases of Olympus EBUS needle assembly malfunction (model NA-201SX-4021/4022). The first case describes needle breakage and the second case reports the separation of shaft of sheath-sliding mechanism.