Mark Yoder

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

Introduction: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography–based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography–based screening and promote its rapid implementation. Methods: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. Results: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2R&agr;, stromal cell-derived factor-1&agr;+&bgr;, tumor necrosis factor &agr;, and macrophage inflammatory protein 1 &agr;. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. Conclusion: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.

Bioactive Lysophosphatidylcholine 16:0 and 18:0 Are Elevated in Lungs of Asthmatic Subjects

Purpose Asthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro-atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids. Methods Eight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry. Results LPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asthma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X). Conclusions The increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma.

Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.

OBJECTIVE Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies. METHODS Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81). RESULTS Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + β), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%. CONCLUSIONS Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.

Stimulated bronchial epithelial cells release bioactive lysophosphatidylcholine 16:0, 18:0, and 18:1.

Purpose In human subjects and animal models with acute and chronic lung injury, the bioactive lysophosphatidylcholine (LPC) is elevated in lung lining fluids. The increased LPC can promote an inflammatory microenvironment resulting in lung injury. Furthermore, pathological lung conditions are associated with upregulated phospholipase A2 (PLA2), the predominant enzyme producing LPC in tissues by hydrolysis of phosphatidylcholine. However, the lung cell populations responsible for increases of LPC have yet to be systematically characterized. The goal was to investigate the LPC generation by bronchial epithelial cells in response to pathological mediators and determine the major LPC species produced. Methods Primary human bronchial epithelial cells (NHBE) were challenged by vascular endothelial growth factor (VEGF) for 1 or 6 h, and condition medium and cells collected for quantification of predominant LPC species by high performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The cells were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for PLA2. The direct effects of LPC in inducing inflammatory activities on NHBE were assessed by transepithelial resistance as well as expression of interleukin-8 (IL-8) and matrix metalloproteinase-1 (MMP-1). Results VEGF stimulation of NHBE for 1 or 6 h, significantly increased concentrations of LPC16:0, LPC18:0, and LPC18:1 in condition medium compared to control. The sPLA2-selective inhibitor (oleyloxyethyl phosphorylcholine) inhibited the VEGF-induced release of LPC16:0 and LPC18:1 and PLA2 activity. In contrast, NHBE stimulated with TNF did not induce LPC release. VEGF did not increase mRNA of PLA2 subtypes sPLA2-X, sPLA2-XIIa, cPLA2-IVa, and iPLA2-VI. Exogenous LPC treatment increased expression of IL-8 and MMP-1, and reduced the transepithelial resistance in NHBE. Conclusions Our findings indicate that VEGF-stimulated bronchial epithelial cells are a key source of extracellular LPCs, which can function as an autocrine mediator with potential to induce airway epithelial inflammatory injury.

Not your typical chronic obstructive pulmonary disease exacerbation: Aspergillus tracheobronchitis in a nonclassical immunocompromised host.

The present study reports on a 72-year-old female initially treated as a presumed chronic obstructive pulmonary disease (COPD) exacerbation, but she was ultimately discovered to have Aspergillus tracheobronchitis. Bronchoscopic findings were characteristic, revealing diffuse plaque-like inflammatory lesions extending from midtrachea into the mainstem bronchi. Evidence suggests that the rise in cases is attributable to the growing number of individuals who are immunocompromised secondary to underlying disease, combined with the expanding number of patients receiving glucocorticoids and immunomodulating medications to treat chronic, nonmalignant disorders. The present observations emphasize the importance of including Aspergillus tracheobronchitis in the differential diagnosis for patients receiving medications with immunosuppressive potential that present with dyspnea, cough, or fever and who fail to improve with empiric antimicrobial therapy.

CT screening for lung cancer: Value of expert review of initial baseline screenings

OBJECTIVE. Appropriate radiologic interpretation of screening CT can minimize unnecessary workup and intervention. This is particularly challenging in the baseline round. We report on the quality assurance process we developed for the International Early Lung Cancer Action Program. MATERIALS AND METHODS. After initial training at the coordinating center, radiologists at 10 participating institutions and at the center independently interpreted the first 100 baseline screenings. The radiologist at the institutions had access to the center interpretations before issuing the final reports. After the first 100 screenings, the interpretations were jointly discussed. This report summarizes the results of the initial 100 dual interpretations at the 10 institutions. RESULTS. The final institution interpretations agreed with the center in 895 of the 1000 interpretations. Compared with the center, the frequency of positive results was higher at eight of the 10 institutions. The most frequent reason of discrepant interpretations was not following the protocol (n = 55) and the least frequent was not identifying a nodule (n = 3). CONCLUSION. The quality assurance process helped focus educational programs and provided an excellent vehicle for review of the protocol with participating physicians. It also suggests that the rate of positive results can be reduced by such measures.

New weapons in the war on tuberculosis.

Tuberculosis continues to be a global threat. Efforts to eradicate this disease are hampered by the long course and potential toxicity of currently available treatment regimens, the increasing prevalence of tuberculosis-HIV coinfection, the evolution of drug resistant organisms, and the lack of a highly effective vaccine. Recent studies have suggested methods to improve the cost effectiveness of existing treatment strategies. Decreasing the relapse rate among high-risk individuals by extending therapy can be balanced by the cost savings of self-administered therapy for low-risk individuals. For the first time in over 30 years, new medications are flowing through the drug discovery pipeline. New agents with activity against slowly dividing bacilli have the potential to shorten the duration of therapy. Many have a more favorable side-effect profile than currently available medications. And even extensively drug-resistant organisms will be susceptible to these secret weapons. The fully sequenced genome of Mycobacterium tuberculosis has been exploited to develop safer and more effective candidate vaccines. Highly immunogenic mycobacterial fragments, revved-up versions of the existing vaccine, and toned-down versions of M. tuberculosis are all in various phases of clinical testing. This expanded arsenal has the potential to deliver a fatal blow to one of humanitys greatest enemies.

Massive hemoptysis in Loeys-Dietz syndrome.

We describe four unrelated individuals with Loeys–Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective‐tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.

Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands (www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. Measurements and Main Results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82‐0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0‐10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502)