@article{3106789,
    title = "Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry — Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort",
    author = "Rulle, U. and Tsourti, Z. and Casanova, R. and Deml, K.-F. and Verbeken, E. and Thunnissen, E. and Warth, A. and Cheney, R. and Sejda, A. and Speel, E.J. and Madsen, L.B. and Nonaka, D. and Navarro, A. and Sansano, I. and Marchetti, A. and Finn, S.P. and Monkhorst, K. and Kerr, K.M. and Haberecker, M. and Wu, C. and Zygoura, P. and Kammler, R. and Geiger, T. and Gendreau, S. and Schulze, K. and Vrugt, B. and Wild, P. and Moch, H. and Weder, W. and Ciftlik, A.T. and Dafni, U. and Peters, S. and Bubendorf, L. and Stahel, R.A. and Soltermann, A.",
    journal = "Journal of Thoracic Oncology",
    year = "2018",
    volume = "13",
    number = "12",
    pages = "1851-1863",
    publisher = "HANLEY & BELFUS-ELSEVIER INC",
    issn = "1556-0864, 1556-1380",
    doi = "10.1016/j.jtho.2018.08.2034",
    keywords = "B Raf kinase;  epidermal growth factor receptor;  K ras protein;  phosphatidylinositol 3 kinase;  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase;  scatter factor receptor;  tyrosine kinase receptor;  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase;  PTEN protein, human;  tumor marker, adult;  aged;  Article;  BRAF gene;  cancer mortality;  cancer prognosis;  cancer staging;  cancer survival;  controlled study;  EGFR gene;  female;  fluorescence in situ hybridization;  histology;  human;  human tissue;  immunohistochemistry;  immunoreactivity;  KRAS gene;  major clinical study;  male;  median survival time;  mortality risk;  mRNA expression level;  non small cell lung cancer;  overall survival;  PIK3CA gene;  prevalence;  priority journal;  prospective study;  protein expression;  receiver operating characteristic;  recurrence free survival;  sensitivity and specificity;  smoking;  tissue microarray;  tumor volume;  cohort analysis;  computer assisted diagnosis;  follow up;  immunohistochemistry;  large cell carcinoma;  lung adenocarcinoma;  lung tumor;  metabolism;  middle aged;  non small cell lung cancer;  pathologist;  pathology;  procedures;  prognosis;  squamous cell carcinoma;  survival rate, Adenocarcinoma of Lung;  Aged;  Biomarkers, Tumor;  Carcinoma, Large Cell;  Carcinoma, Non-Small-Cell Lung;  Carcinoma, Squamous Cell;  Cohort Studies;  Diagnosis, Computer-Assisted;  Female;  Follow-Up Studies;  Humans;  Immunohistochemistry;  Lung Neoplasms;  Male;  Middle Aged;  Pathologists;  Prognosis;  PTEN Phosphohydrolase;  Survival Rate;  Tissue Array Analysis",
    abstract = "Introduction: Phosphatase and tensin homolog (PTEN) loss is frequently observed in NSCLC and associated with both phosphoinositide 3-kinase activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable readout, but lacks standardized staining protocol and cutoff value. Methods: After an external quality assessment using SP218, 138G6 and 6H2.1 anti-PTEN antibodies, scored on webbook and tissue microarray, the European Thoracic Oncology Platform cohort samples (n = 2245 NSCLC patients, 8980 tissue microarray cores) were stained with SP218. All cores were H-scored by pathologists and by computerized pixel-based intensity measurements calibrated by pathologists. Results: All three antibodies differentiated six PTEN+ versus six PTEN- cases on external quality assessment. For 138G6 and SP218, high sensitivity and specificity was found for all H-score threshold values including prospectively defined 0, calculated 8 (pathologists), and calculated 5 (computer). High concordance among pathologists in setting computer-based intensities and between pathologists and computer in H-scoring was observed. Because of over-integration of the human eye, pixel-based computer H-scores were overall 54% lower. For all cutoff values, PTEN- was associated with smoking history, squamous cell histology, and higher tumor stage (p < 0.001). In adenocarcinomas, PTEN- was associated with poor survival. Conclusion: Calibration of immunoreactivity intensities by pathologists following computerized H-score measurements has the potential to improve reproducibility and homogeneity of biomarker detection regarding epitope validation in multicenter studies. © 2018 International Association for the Study of Lung Cancer"
}