Identification of an autoantibody panel to separate lung cancer from smokers and nonsmokers

<p>Abstract</p> <p>Background</p> <p>Sera from lung cancer patients contain autoantibodies that react with tumor associated antigens (TAAs) that reflect genetic over-expression, mutation, or other anomalies of cell cycle, growth, signaling, and metabolism pathways.</p> <p>Methods</p> <p>We performed immunoassays to detect autoantibodies to ten tumor associated antigens (TAAs) selected on the basis of previous studies showing that they had preferential specificity for certain cancers. Sera examined were from lung cancer patients (22); smokers with ground-glass opacities (GGOs) (46), benign solid nodules (55), or normal CTs (35); and normal non-smokers (36). Logistic regression models based on the antibody biomarker levels among the high risk and lung cancer groups were developed to identify the combinations of biomarkers that predict lung cancer in these cohorts.</p> <p>Results</p> <p>Statistically significant differences in the distributions of each of the biomarkers were identified among all five groups. Using Receiver Operating Characteristic (ROC) curves based on age, c-myc, Cyclin A, Cyclin B1, Cyclin D1, CDK2, and survivin, we obtained a sensitivity = 81% and specificity = 97% for the classification of cancer vs smokers(no nodules, solid nodules, or GGO) and correctly predicted 31/36 healthy controls as noncancer.</p> <p>Conclusion</p> <p>A pattern of autoantibody reactivity to TAAs may distinguish patients with lung cancer versus smokers with normal CTs, stable solid nodules, ground glass opacities, or normal healthy never smokers.</p

CT Scan Screening for Lung Cancer: Risk Factors for Nodules and Malignancy in a High-Risk Urban Cohort

Low-dose computed tomography (CT) for lung cancer screening can reduce lung cancer mortality. The National Lung Screening Trial reported a 20% reduction in lung cancer mortality in high-risk smokers. However, CT scanning is extremely sensitive and detects non-calcified nodules (NCNs) in 24-50% of subjects, suggesting an unacceptably high false-positive rate. We hypothesized that by reviewing demographic, clinical and nodule characteristics, we could identify risk factors associated with the presence of nodules on screening CT, and with the probability that a NCN was malignant.We performed a longitudinal lung cancer biomarker discovery trial (NYU LCBC) that included low-dose CT-screening of high-risk individuals over 50 years of age, with more than 20 pack-year smoking histories, living in an urban setting, and with a potential for asbestos exposure. We used case-control studies to identify risk factors associated with the presence of nodules (n=625) versus no nodules (n=557), and lung cancer patients (n=30) versus benign nodules (n=128).The NYU LCBC followed 1182 study subjects prospectively over a 10-year period. We found 52% to have NCNs >4 mm on their baseline screen. Most of the nodules were stable, and 9.7% of solid and 26.2% of sub-solid nodules resolved. We diagnosed 30 lung cancers, 26 stage I. Three patients had synchronous primary lung cancers or multifocal disease. Thus, there were 33 lung cancers: 10 incident, and 23 prevalent. A sub-group of the prevalent group were stable for a prolonged period prior to diagnosis. These were all stage I at diagnosis and 12/13 were adenocarcinomas.NCNs are common among CT-screened high-risk subjects and can often be managed conservatively. Risk factors for malignancy included increasing age, size and number of nodules, reduced FEV1 and FVC, and increased pack-years smoking. A sub-group of screen-detected cancers are slow-growing and may contribute to over-diagnosis and lead-time biases

Role of small airway dysfunction in unexplained exertional dyspnoea

Background Isolated small airway abnormalities may be demonstrable at rest in patients with normal spirometry; however, the relationship of these abnormalities to exertional symptoms remains uncertain. This study uses an augmented cardiopulmonary exercise test (CPET) to include evaluation of small airway function during and following exercise to unmask abnormalities not evident with standard testing in individuals with dyspnoea and normal spirometry. Methods Three groups of subjects were studied: 1) World Trade Center (WTC) dust exposure (n=20); 2) Clinical Referral (n=15); and Control (n=13). Baseline evaluation included respiratory oscillometry. Airway function during an incremental workload CPET was assessed by: 1) tidal flow versus volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and 2) post-exercise spirometry and oscillometry to evaluate for airway hyperreactivity. Results All subjects demonstrated normal baseline forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). Dyspnoea was reproduced during CPET in WTC and Clinical Referral groups versus Control without abnormality in respiratory pattern and minute ventilation. Tidal flow–volume curves uncovered expiratory flow limitation and/or dynamic hyperinflation with increased prevalence in WTC and Clinical Referral versus Control (55%, 87% versus 15%; p<0.001). Post-exercise oscillometry uncovered small airway hyperreactivity with increased prevalence in WTC and Clinical Referral versus Control (40%, 47% versus 0%, p<0.05). Conclusions We uncovered mechanisms for exertional dyspnoea in subject with normal spirometry that was attributable to either small airway dysfunction during exercise and/or small airway hyperreactivity following exercise. The similarity of findings in WTC environmentally exposed and clinically referred cohorts suggests broad relevance for these evaluations

Histogram of the number of CTs performed per individual.

<p>Over 70% of participants had at least one follow-up CT. A total of 345 had 1 CT, 183 had 2 CTs and 654 had 3 or more CTs. Those that did not have follow-ups were individuals with no nodules on initial CT who chose not to return or individuals who were not yet due for follow-up by the end of the study period.</p

Lung Cancer Cases Compared with All Screened.

*<p>3 patients diagnosed with 2 primaries. 2 with synchronous adenoca, 1 with prevalence adenocarcinoma and incidence small cell.</p

Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease

Rationale: Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease. Objectives: In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. Methods: During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events. Measurements and Main Results: The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. −25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation. Conclusions: Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236)

The Clinical Features of Bronchiectasis Associated with Alpha-1 Antitrypsin Deficiency, Common Variable Immunodeficiency and Primary Ciliary Dyskinesia--Results from the U.S. Bronchiectasis Research Registry

Objective : This study compares and contrasts the clinical features of non-cystic fibrosis bronchiectasis with 3 uncommon disorders known to be associated with bronchiectasis but with distinctly different underlying defined pathophysiologic derangements, namely severe alpha-1 antitrypsin deficiency (AATD), common variable immunodeficiency (CVI) and primary ciliary dyskinesia (PCD). Methods : The Bronchiectasis Research Registry provides a central database for studying patients with non-cystic fibrosis bronchiectasis. This report consists of information from 13 U.S. sites pertaining to the 3 study diagnoses. Patients with AATD (SZ and ZZ phenotypes only), CVI (patients with IgG≤500), PCD (history of physician diagnosed Kartagener’s syndrome or PCD), and patients with confirmed absence of the above 3 diagnoses (idiopathic control group) were included in the study. Descriptive statistics were computed for the main demographic and clinical characteristics of the sample stratified by group. Values between the groups were compared using Kruskal-Wallis test, and Chi-squared/ Fisher’s exact tests respectively. The significance level was set at 0.05. Software SAS 9.4 was used to perform the statistical analyses. Results : Of the 2170 participants in the database enrolled as of January 2017, 615 respondents had sufficient data and were included in the analyses. Patients with PCD (n=79, mean age 41.9 years [standard deviation (SD)=14.5]) were significantly younger than patients with AATD (n=58, mean age 66.9 [SD=10.7]), CVI (n=18, mean age 66.7 years [SD=10.5]) or the idiopathic group (n=460, mean age 64.2 [SD=15.9]), p <.0001. Compared to other groups, those with PCD had lower pulmonary function (forced expiratory volume in 1 second [FEV 1 ] forced vital capacity [FVC] and FEV1/FVC ratio) ( p <0.01), and a greater proportion of them reported having exacerbations and/or hospitalizations in the past 2 years ( p <0.01). Overall, Pseudomonas aeruginosa and Staphylococcus aureus were the organisms most commonly isolated from sputum. Mycobacterial infection was most commonly reported in those with AATD. Conclusions : This report from the U.S. Bronchiectasis Research Registry compares and contrasts differences in the clinical features of patients suffering from 3 rare conditions, with different underlying causes, to those without. The group with PCD had more symptoms, greater morbidity, lower lung function and more commonly were infected by Pseudomonas aeruginosa . A greater percentage of those with AATD reported mycobacterial lung involvement