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R.L. Keith



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    MA01 - Improvement and Implementation of Lung Cancer Screening (ID 368)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      MA01.02 - Non-Invasive LuCED® Test for Endobronchial Dysplasia, Enabling Chemoprevention Therapy with Drugs Such as Iloprost (ID 3866)

      11:00 - 12:30  |  Author(s): R.L. Keith

      • Abstract
      • Presentation
      • Slides

      Background:
      The LuCED test for early stage lung cancer detects rare abnormal cells that are exfoliated from tumors into sputum and promotes cancer case detection with >92% sensitivity and >95% specificity. Additionally, the LuCED test detects endobronchial lung dysplasia to triage patients with pre-cancer to chemoprevention therapy involving drugs such as Iloprost that show potential for reversing dysplasia. This test is complementary to lung cancer screening methods such as LDCT that do not detect dysplasia. We discuss the performance of the LuCED test for the non-invasive detection of endobronchial dysplasia.

      Methods:
      We analyzed 23,188 normal, 690 cancer, and 65 moderate/severe dysplasia cells from patient sputum. Each individual cell was imaged in 3D using the Cell-CT. Cells were analyzed to measure 594 3D structural biomarkers. Classifiers were developed with cytopathology as the gold standard to predict stages of carcinogenesis, from normal to dysplasia and cancer. The classifier output was binned into two diagnostic indications: 1) cancer vs. all other cell types; and 2) moderate/severe dysplasia vs. all other cell types.

      Results:
      Areas under ROC curves for the two diagnostic bins were both = 0.993. Thresholds were chosen to yield case specificity >95%. Using these thresholds, cell classification sensitivity of 75% was measured for cancer and dysplasia detection. Since abnormal sputum typically contains at least three abnormal cells the cancer case detection sensitivity is at least {100% x [1 – (1 - 0.75)[3]]} = 98%.Figure 1 Figure 1 shows ROC curves plus examples of cells imaged in 3D by the Cell-CT.



      Conclusion:
      This study demonstrates the feasibility of using the LuCED test to detect endobronchial dysplasia in the lung, achieving an estimated 98% case sensitivity and 95% case specificity. Future efforts will include testing on independent sets. Importantly, the non-invasive detection of dysplasia by LuCED testing may enable chemoprevention of lung cancer using drugs such as Iloprost.

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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-084 - Polo-Like Kinase 1 (PLK1) Inhibition Decreases Mutational Activity in Bronchial Epithelial Cells Exposed to Tobacco Carcinogens (ID 6206)

      14:30 - 15:45  |  Author(s): R.L. Keith

      • Abstract

      Background:
      Persistence of bronchial dysplasia (BD) is associated with increased risk for the development of squamous cell carcinoma (SCC) of the lung. A comparison of persistent and regressive BD demonstrated that alterations in gene expression can distinguish these types of lesions. Using the genes that differentiate persistent and regressive BD we have identified PLK1 as a key mediator of persistence and have hypothesized that the role it plays in abrogating G2-M cell cycle arrest in the presence of mutational alterations may be central to progression of premalignant airway lesions to invasive SCC.

      Methods:
      Cultures of the bronchial epithelium derived BEAS-2B (B2B) cell line were exposed to airway mutagens (cigarette smoke condensate [CSC, Kentucky Reference Cigarette 3R4F] or Benzo[A]pyrene, [BaP]) alone or in the presence of 100 nM PLK1 inhibitor Volasertib. Following treatment, clones were selected by ring isolation and DNA was collected to assess mutational events as compared to untreated controls using the TruSightOne targeted next generation sequencing panel (12 megabase coverage, >4800 genes, Illumina, San Diego, CA). Modal distribution of mutation frequencies indicated that ring clones were composed of between 1 - 3 distinct clones. Mutation rates were calculated using these adjusted clone counts for standardization.

      Results:
      Using the untreated B2B cultures as reference sequence, CSC or BaP alone induced mean incidences of mutations of 15.7 and 60.9 per clone, respectively, although the induction of fewer mutations by CSC made accurate estimates of clonal numbers more difficult. B2B cultures treated with the same concentration and duration of mutagen in the presence of Volasertib showed mean mutational incidences of 13 and 17 per clone, respectively. The ratio of mutation rate for the CSC and BaP treated groups with versus without Volasertib were 0.83 and 0.28, respectively. All mutations detected were single nucleotide variants and characteristic patterns of base changes were noted between mutagen groups with C>A and G>T transversions being more prominent in BaP treated cultures. Ongoing analyses using whole genome sequencing will allow for more accurate enumeration of clones represented and a richer assessment of mutation rates including rearrangements and copy number variants in mutagen treated cells in the presence and absence of PLK1 inhibition.

      Conclusion:
      Preliminary analyses of bronchial epithelial cell cultures treated with mutagens show reduction of BaP induced mutations in the presence of PLK1 inhibition. The results suggest PLK1 overexpression in BD may promote genomic instability.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-032 - Oral Pioglitazone for the Chemoprevention of Lung Cancer in Current and Former Smokers (ID 4395)

      14:30 - 15:45  |  Author(s): R.L. Keith

      • Abstract

      Background:
      Clinical Trial with Data Analysis in Progress

      Methods:
      Subjects (n=90) were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed at trial entry with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months, followed by a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

      Results:
      Final data analysis is pending

      Conclusion:
      clinical trial with data analysis in progress