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Publisher: Elsevier   (Total: 3162 journals)

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Showing 1 - 200 of 3162 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 33, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 23, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 95, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 36, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 411, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 249, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 6)
Acute Pain     Full-text available via subscription   (Followers: 14, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 16, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 9, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 148, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 12, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 23, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 32, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 8, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 3)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in Digestive Medicine     Open Access   (Followers: 9)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 28, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 44, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 58, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 16, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 21, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 17, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 11)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 9)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 395, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 10, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 33, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 46, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 340, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 448, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 42, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 3)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 9)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 50, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 54, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 45, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 28, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 34, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 46)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 209, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 63, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 38, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 62, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 17, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 43, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 175, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 11, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 192, SJR: 1.58, CiteScore: 3)

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Journal Cover
Lung Cancer
Journal Prestige (SJR): 1.75
Citation Impact (citeScore): 4
Number of Followers: 14  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0169-5002
Published by Elsevier Homepage  [3162 journals]
  • Chemerin as a biomarker at the intersection of inflammation, coagulation,
           fibrinolysis and metabolism in resectable Non-Small Cell Lung Cancer
    • Abstract: Publication date: Available online 10 October 2018Source: Lung CancerAuthor(s): George P. Sotiropoulos, Maria Dalamaga, Georgios Antonakos, Ioanna Marinou, Evaggelos Vogiatzakis, Marianna Kotopouli, Irene Karampela, Gerasimos Socrates Christodoulatos, Antigoni Lekka, Athanasios G. Papavassiliou ObjectivesChemerin is an emerging adipocytokine at the intersection of inflammation, chemotaxis, thrombosis, fibrinolysis and metabolism. Our aims were 1) to explore circulating chemerin in resectable non-small cell lung cancer (NSCLC) taking into account its several interfaces; 2) to study its diagnostic potential; and 3) to assess its associations with clinicopathological features of NSCLC.Materials and MethodsIn a large case-control study, serum chemerin, insulin resistance and lipid parameters, classic adipocytokines, inflammatory, coagulation, fibrinolysis and tumor biomarkers were determined in 110 consecutive patients with resectable NSCLC and 110 healthy controls matched on age (± 5 years), gender and date of blood draw (± 1 month).ResultsNSCLC cases exhibited significantly elevated circulating chemerin compared to controls (p 
       
  • Real-life treatment practice for malignant pleural mesothelioma in Belgium
    • Abstract: Publication date: Available online 9 October 2018Source: Lung CancerAuthor(s): Michael Rosskamp, Gilles Macq, Kristiaan Nackaerts, Marleen Praet, Liesbet Van Eycken, Jan P Van Meerbeeck, Harlinde De Schutter ObjectivesMalignant pleural mesothelioma (MPM) is a rare and aggressive cancer, for which treatment is often limited to palliative combination chemotherapy. Multimodality-therapy, including radical surgery, is largely restricted to clinical trials, leaving its benefit currently unclear. This study aimed to get a comprehensive view on real-world MPM treatment at the Belgian population level, to assess survival and to identify prognostic factors.Materials and MethodsThe study period covered the incidence years 2004-2012 (N = 1,453). Starting from the Belgian Cancer Registry, additional information regarding patient characteristics, diagnosis and treatment was retrieved from multiple data sources. Adjusted cox proportional-hazard regression models using time-dependent covariates were performed to assess survival in relation to treatment patterns and centre volume.ResultsSixty-nine percent of patients underwent tumour-directed treatment, mostly cisplatin-pemetrexed chemotherapy. Radical surgery was mainly performed in younger patients with epithelioid subtype. Centre volume, surgery and chemotherapy showed a positive relation with survival in univariable analyses, but only chemotherapy remained significantly relevant in multivariable analyses. Younger patients, females, and epithelioid subtypes also independently had a better survival.ConclusionThis large population-based study provides insights in MPM treatment practice in Belgium. Centre volume and surgery being related to survival in univariable analyses, only chemotherapy remained prognostic after adjustment.
       
  • Clinical utility of a blood-based EGFR mutation test in patients receiving
           first-line erlotinib therapy in the ENSURE, FASTACT-2, and ASPIRATION
           studies
    • Abstract: Publication date: Available online 9 October 2018Source: Lung CancerAuthor(s): Yi-Long Wu, Victor Lee, Chong-Kin Liam, Shun Lu, Keunchil Park, Vichien Srimuninnimit, Jie Wang, Caicun Zhou, Anita Appius, Peter Button, Gregory Hooper, John F. Palma, Katja Schulze, Sidney Scudder, David S. Shames, Anny-Yue Yin, Guili Zhang, Tony Mok, on behalf of the ENSURE, FASTACT-2, and ASPIRATION Investigators ObjectivePatients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas® EGFR Mutation Test v2.Materials and methodsTwo EGFR mutation tests, a tissue-based assay (cobas® v1) and a tissue- and blood-based assay (cobas® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden.ResultsPatients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8–76.1) and a specificity of 97.9% (95% CI 96.0–99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors.ConclusionsBlood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations.
       
  • Clinicopathological and genomic comparisons between different histologic
           components in combined small cell lung cancer and non-small cell lung
           cancer
    • Abstract: Publication date: Available online 9 October 2018Source: Lung CancerAuthor(s): Mong-Wei Lin, Kang-Yi Su, Te-Jen Su, Chia-Ching Chang, Jing-Wei Lin, Yi-Hsuan Lee, Sung-Liang Yu, Jin-Shing Chen, Min-Shu Hsieh ObjectiveHistologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined non-small cell lung cancer (NSCLC)/SCLC have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment.Materials and MethodsFour patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel.ResultsThe distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases.ConclusionsOur data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways.
       
  • Comparative study of programmed cell death ligand-1 immunohistochemistry
           assays using 22C3 and 28-8 antibodies for non-small cell lung cancer:
           analysis of 420 surgical specimens from Japanese patients
    • Abstract: Publication date: Available online 6 October 2018Source: Lung CancerAuthor(s): Tomohito Saito, Koji Tsuta, Mitsuaki Ishida, Hironori Ryota, Yuki Takeyasu, Kento J. Fukumoto, Hiroshi Matsui, Yohei Taniguchi, Hiroaki Yanagimoto, Takayasu Kurata, Tomohiro Murakawa ObjectivesMultiple programmed cell death ligand-1 (PD-L1) immunohistochemistry assays are currently used as companion or complementary diagnostic tools for anti-programmed cell death-1 immunotherapies. We aimed to characterize two PD-L1 immunohistochemistry assays (Dako 22C3 and 28-8) for non-small cell lung cancer (NSCLC) in clinical laboratories.Materials and MethodsSurgical specimens from 420 patients with pathological stages IAIIIA NSCLC were investigated. The archived samples were freshly cut into 5-μm-thick sections stained with antibodies 22C3 and 28-8, and tumoral PD-L1 expression was evaluated in two clinical laboratories, respectively. Overall, positive, and negative percent agreement (OPA, PPA, and NPA, respectively) at specified PD-L1 cutoffs were calculated to assess the concordance between 22C3 and 28-8 assays.ResultsTumoral PD-L1 expression of ≥ 1 % was detected by either 22C3 or 28-8 assays in 176 cases (41.9%), whereas 22C3 revealed a significantly higher tumoral PD-L1 expression compared to 28-8 (median 30 % vs. 10 %, p 
       
  • Use of health insurance data to identify and quantify the prevalence of
           main comorbidities in lung cancer patients
    • Abstract: Publication date: Available online 3 October 2018Source: Lung CancerAuthor(s): David Jegou, Cécile Dubois, Viki Schillemans, Sabine Stordeur, Cindy De Gendt, Cécile Camberlin, Leen Verleye, France Vrijens BackgroundIdentifying comorbidities in lung cancer patients is a complex process in population-based studies and no gold standard exists. The current study aims to identify and measure the main comorbidities using administrative health insurance data, which were available on a population-based level.MethodA literature search was conducted to identify comorbidities in lung cancer patients and to select Anatomical Therapeutic Chemical codes to measure them. For each patient, the volume of delivered relevant drugs for each comorbidity in the year preceding the diagnosis of lung cancer was computed, based on the Defined Daily Doses reimbursed. Case definition rules were set by comparing the identification of comorbidities via health insurance data with the reporting of them in the medical files in a sample of hospitals.ResultsFour comorbidities were identified: chronic respiratory diseases, chronic cardiovascular diseases, diabetes mellitus and renal diseases. A very good to moderate agreement between the prevalence based on medical files versus health insurance data was obtained for diabetes mellitus (kappa = 0.83), chronic cardiovascular diseases (kappa = 0.64), chronic respiratory diseases (kappa = 0.48) but not for renal diseases (kappa = 0.22). Because only 27% of patients having renal diseases recorded in the medical files were identified using health insurance data, this comorbidity was not withheld. Among 12,839 lung cancer patients diagnosed in 2010-2011 in Belgium, 29.7% had chronic respiratory diseases, 57.5% had chronic cardiovascular diseases and 14.1% had diabetes mellitus.DiscussionThis study showed that it was possible to capture three major comorbidities in lung cancer patients using administrative health data, namely, diabetes mellitus, chronic cardiovascular diseases, and chronic respiratory diseases. However, the agreement was only moderate for the last one. A prerequisite for using this methodology is that administrative health data are available for all patients.
       
  • Corrigendum to “Routine preoperative brain CT in resectable non-small
           cell lung cancer—Ten years experience from a tertiary UK thoracic
           center” [Lung Cancer 122 (August) (2018) 195–199]
    • Abstract: Publication date: Available online 1 October 2018Source: Lung CancerAuthor(s): Tomasz Matys, Rosalyn Drury, Sarojini David, Doris M. Rassl, Wendi Qian, Robert C. Rintoul, Nicholas J. Screaton
       
  • Proposal on incorporating Lymphovascular Invasion as a T-descriptor for
           Stage I Lung Cancer
    • Abstract: Publication date: Available online 1 October 2018Source: Lung CancerAuthor(s): Shuyuan Wang, Bo Zhang, Jie Qian, Rong Qiao, Jianlin Xu, Lele Zhang, Yiming Zhao, Yanwei Zhang, Rui Wang, Ruiying Zhao, Baohui HanABSTRACTBackgroundLymphovascular invasion (LVI) and Visceral Pleural Invasion (VPI) have been reported to be risk factors for stage I Non-Small Cell Lung Cancer (NSCLC). However, only VPI was incorporated into the current 8th Tumor–Node–Metastasis (TNM) classification. This study aimed to explore the prognostic effect of LVI and VPI on TNM staging in pathological stage I NSCLC.MethodWe retrospectively reviewed 2633 consecutive p-stage I NSCLC patients in the Shanghai Chest Hospital (2008-2012). By using the Kaplan–Meier method and Cox proportional hazard regression model, we identified the correlations between LVI, VPI, and clinical outcomes in p-stage 1 NSCLC.ResultsOf all 2633 p-stage I NSCLC patients, 222 were pathologically diagnosed with LVI and 836 pathologically with VPI. The 5-year recurrence free survival (RFS) and overall survival (OS) rates of patients with LVI was significantly worse compared to those without LVI (61.2% vs 82.0%, p 
       
  • Receipt of Recommended Surveillance with Imaging in Elderly Survivors of
           Early Stage Non-small Cell Lung Cancer
    • Abstract: Publication date: Available online 1 October 2018Source: Lung CancerAuthor(s): Jyoti Malhotra, David Rotter, Salma K. Jabbour, Joseph Aisner, Yong Lin, Sharon Manne, Kitaw Demissie PurposeEarly-stage lung cancer survivors remain at high risk for recurrence or second cancers. We measured the rates and determinants of regular surveillance imaging in early-stage non-small cell lung cancer (NSCLC) survivors.MethodsPatients (diagnosed 2001-2011) with resected stage I and II NSCLC were identified from the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Patients were censored at recurrence/second cancer diagnosis, loss to follow-up or death. Receipt of a scan during the surveillance periods of 7-18, 19-30, 31-42 and 43-60 months from date of surgery was assessed.ResultsOf 10,680 survivors assessed during the 18-month surveillance period, 71% received imaging in first 18 months. Only 56% and 43% continued to receive regular imaging by 30-month and 60-month of follow-up, respectively. Survivors were less likely to receive imaging if they were older, black, unmarried, received no adjuvant therapy, had stage I disease (vs. stage II) or were diagnosed before 2006. In adjusted analysis, survivors who received recommended imaging up to 18 months from surgery experienced better survival compared to survivors who did not (HR 0.92; 95% CI 0.85-0.99). Survival benefit was also observed in survivors who underwent regular imaging up to 5 years from surgery (HR 0.68; 95% CI 0.60-0.78).ConclusionsMore than half the lung cancer survivors received less than the recommended long-term surveillance imaging. Long-term adherence to surveillance is associated with improved survival. Our study provides evidence to support the current clinical guidelines for surveillance for lung cancer survivors that are primarily consensus-based at present.
       
  • Reply to Dickhoff et al. from authors of ‘Induction chemoradiotherapy
           versus chemotherapy alone for superior sulcus lung cancer’
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): Lary A. Robinson, Tawee Tanvetyanon, Deanna Grubbs, Scott Antonia, Ben Creelan, Jacques Fontaine, Eric Toloza, Robert Keenan, Thomas Dilling, Craig W. Stevens, K. Eric Sommers, Frank Vrionis
       
  • In Regard to Robinson et al: Induction chemoradiotherapy versus
           chemotherapy alone for superior sulcus lung cancer
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): C. Dickhoff, M. Dahele
       
  • Heterogeneous MET gene copy number and EGFR mutation elicit discordant
           responses to crizotinib between primary and metastatic lesions in
           erlotinib-resistant lung adenocarcinoma
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): Katsuhiro Yoshimura, Masato Karayama, Yusuke Inoue, Tomoaki Kahyo, Naoki Inui, Masato Maekawa, Haruhiko Sugimura, Takafumi Suda
       
  • Adjuvant treatment patterns and outcomes in patients with stage IB-IIIA
           non-small cell lung cancer in France, Germany, and the United Kingdom
           based on the LuCaBIS burden of illness study
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): Christos Chouaid, Sarah Danson, Stefan Andreas, Obukohwo Siakpere, Laure Benjamin, Rainer Ehness, Marie-Hélène Dramard-Goasdoue, Janina Barth, Hans Hoffmann, Vanessa Potter, Fabrice Barlesi, Mark Price, Costel Chirila, Kelly Hollis, Carolyn Sweeney, Sorrel Wolowacz, James A. Kaye, Ilias Kontoudis ObjectivesTo inform health-technology assessments of new adjuvant treatments, we describe treatment patterns in patients with complete resection of stage IB-IIIA non-small cell lung cancer (NSCLC) in France, Germany, and the United Kingdom (UK).Materials and methodsData were collected via medical record abstraction. Patients were aged ≥18 years with completely resected stage IB-IIIA NSCLC, diagnosed between 01 January 2009 and 31 December 2011. Median follow-up was 26 months. Adjuvant treatment patterns and clinical outcomes were summarized descriptively.ResultsAmong the 831 patients studied, 239 (29%) had stage IB disease, 179 (22%) had stage IIA disease, 165 (20%) had stage IIB disease, and 248 (30%) had stage IIIA disease. Adjuvant systemic therapy was received by 402 patients (48.4%), (France, 61.8%; Germany, 51.9%; UK, 33.4%). Use of adjuvant therapy increased with increasing stage of disease. Cisplatin/vinorelbine and carboplatin/vinorelbine were the most frequently prescribed adjuvant regimens. Median disease-free survival was 48.0 months (95% confidence interval [CI] 42.3–not estimable); the 25th percentile was 13.2 months (95% CI, 11.0–15.3). 204 patients (24%) died during the follow-up period. The median overall survival was not reached, the 25th percentile was 31.2 months (95% CI 26.8–36.0 months). 272 patients (33%) had disease recurrence during the follow-up period. For 86 of those patients, the first recurrence was local or regional with no distant metastasis and 14 had further progression to metastatic disease during the follow-up time. For the other 186 patients, the first recurrence involved distant metastases. A total of 200 patients had metastatic disease at any time during study follow-up.ConclusionsLess than half the patients with stage IB-IIIA NSCLC in this observational study received adjuvant systemic therapy. A high rate of first recurrence with distant metastatic disease was observed, emphasising the need for more effective systemic adjuvant therapies in this population.
       
  • Economic burden of resected (stage IB-IIIA) non-small cell lung cancer in
           France, Germany and the United Kingdom: A retrospective observational
           study (LuCaBIS)
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): Stefan Andreas, Christos Chouaid, Sarah Danson, Obukohwo Siakpere, Laure Benjamin, Rainer Ehness, Marie-Hélène Dramard-Goasdoue, Janina Barth, Hans Hoffmann, Vanessa Potter, Fabrice Barlesi, Costel Chirila, Kelly Hollis, Carolyn Sweeney, Mark Price, Sorrel Wolowacz, James A. Kaye, Ilias Kontoudis ObjectivesNew adjuvant treatments are being developed for patients with resected non-small cell lung cancer (NSCLC). Due to scarcity of real-world data available for treatment costs and resource utilization, health technology and cost-effectiveness assessments can be limited. We estimated the burden and cost-of-illness associated with completely resected stage IB-IIIA NSCLC in France, Germany and the United Kingdom (UK).Materials and methodsEligible patients were aged ≥18 years with completely resected stage IB-IIIA NSCLC between August 2009 and July 2012. Patients (living or deceased) were enrolled at clinical sites by a systematic sampling method. Data were obtained from medical records and patient surveys. Direct, indirect and patient out-of-pocket expenses were estimated by multiplying resource use by country-specific unit costs. National annual costs were estimated based on disease prevalence data available from published sources.Results39 centers provided data from 831 patients of whom patient surveys were evaluable in 306 patients. Median follow-up was 26 months. The mean total direct costs per patient during follow-up were: €19,057 (France), €14,185 (Germany), and €8377 (UK). The largest cost drivers were associated with therapies received (€12,375 France; €3694 UK), and hospitalization/emergency costs (€7706 Germany). Monthly direct costs per patient were the highest during the distant metastasis/terminal illness phase in France (€15,562) and Germany (€6047) and during the adjuvant treatment period in the UK (€2790). Estimated mean total indirect costs per patient were: €696 (France), €2476 (Germany), and €1414 (UK). Estimates for the annual national direct cost were €478.4 million (France), €574.6 million (Germany) and €325.8 million (UK).ConclusionTo our knowledge, this is the first comprehensive study describing the burden of illness for patients with completely resected stage IB-IIIA NSCLC. The economic burden was substantial in all three countries. Treatment of NSCLC is associated with large annual national costs, mainly incurred during disease progression.
       
  • Multi-centre prospective study on diagnosing subtypes of lung cancer by
           exhaled-breath analysis
    • Abstract: Publication date: Available online 29 September 2018Source: Lung CancerAuthor(s): S. Kort, M.M. Tiggeloven, M. Brusse-Keizer, J.W. Gerritsen, J.H. Schouwink, E. Citgez, F.H.C. de Jongh, S. Samii, J. van der Maten, M. van den Bogart, J. van der Palen ObjectivesLung cancer is a leading cause of mortality. Exhaled-breath analysis of volatile organic compounds (VOC’s) might detect lung cancer early in the course of the disease, which may improve outcomes. Subtyping lung cancers could be helpful in further clinical decisions.Materials and methodsIn a prospective, multi-centre study, using 10 electronic nose devices, 144 subjects diagnosed with NSCLC and 146 healthy subjects, including subjects considered negative for NSCLC after investigation, breathed into the Aeonose™ (The eNose Company, Zutphen, Netherlands). Also, analyses into subtypes of NSCLC, such as adenocarcinoma (AC) and squamous cell carcinoma (SCC), and analyses of patients with small cell lung cancer (SCLC) were performed.ResultsChoosing a cut-off point to predominantly rule out cancer resulted for NSCLC in a sensitivity of 94.4%, a specificity of 32.9%, a positive predictive value of 58.1%, a negative predictive value (NPV) of 85.7%, and an area under the curve (AUC) of 0.76. For AC sensitivity, PPV, NPV, and AUC were 81.5%, 56.4%, 79.5%, and 0.74, respectively, while for SCC these numbers were 80.8%, 45.7%, 93.0%, and 0.77, respectively. SCLC could be ruled out with a sensitivity of 88.9% and an NPV of 96.8% with an AUC of 0.86.ConclusionElectronic nose technology with the Aeonose™ can play an important role in rapidly excluding lung cancer due to the high negative predictive value for various, but not all types of lung cancer. Patients showing positive breath tests should still be subjected to further diagnostic testing.
       
  • A combination of MTAP and BAP1 immunohistochemistry is effective for
           distinguishing sarcomatoid mesothelioma from fibrous pleuritic
    • Abstract: Publication date: Available online 26 September 2018Source: Lung CancerAuthor(s): Yoshiaki Kinoshita, Makoto Hamasaki, Masayo Yoshimura, Shinji Matsumoto, Ayuko Sato, Tohru Tsujimura, Hitoshi Ueda, Satoshi Makihata, Fumiaki Kato, Akinori Iwasaki, Kazuki Nabeshima ObjectivesHistologic diagnosis of malignant pleural mesothelioma (MPM) is not always straightforward. Loss of BRCA1-associated protein 1 (BAP1) expression as detected by immunohistochemistry (IHC) (BAP1 IHC) and homozygous deletion (HD) of 9p21 as detected by fluorescencein situ hybridization (FISH) (9p21 FISH) are effective for distinguishing malignant mesothelial proliferation from benign proliferation. We have previously reported that immunohistochemical expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, is correlated with the deletion status of 9p21 FISH in MPM tissues. In this study, we investigated whether a combination of MTAP and BAP1 IHC could distinguish sarcomatoid MPM from fibrous pleuritis.Materials and MethodsWe examined IHC expressions of MTAP and BAP1 and 9p21 FISH in sarcomatoid/desmoplastic (n = 18) and biphasic MPM (n = 12) and in fibrous pleuritis (n = 17). In biphasic MPM, only sarcomatoid components were evaluated for IHC and FISH. The sensitivity and specificity of each detection assay for discriminating MPM cases from fibrous pleuritis was determined. In addition, we compared the IHC expression of MTAP with the deletion status of 9p21 FISH.ResultsMTAP IHC and BAP1 IHC showed 80% and 36.7% sensitivity, respectively, and both showed 100% specificity in differentiating MPM from fibrous pleuritis. A combination of MTAP and BAP1 IHC yielded greater sensitivity (90%) than that detected for MTAP IHC alone or BAP1 IHC alone. Moreover, a high degree of concordance was observed between the results of MTAP IHC and HD of 9p21 FISH (κ = 0.63).ConclusionsWith an accurate interpretation of results, combined MTAP and BAP1 IHC is a reliable and effective method for distinguishing sarcomatoid MPM from fibrous pleuritis.
       
  • LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with
           prognostic implications for early-stage disease
    • Abstract: Publication date: Available online 24 September 2018Source: Lung CancerAuthor(s): Terese Karlsson, Samuel Kvarnbrink, Camilla Holmlund, Johan Botling, Patrick Micke, Roger Henriksson, Mikael Johansson, Håkan Hedman ObjectivesThe human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.Materials and methodsAn yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.ResultsIn the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.ConclusionThese findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.
       
  • Comment on: Pneumonitis in advanced non-small-cell lung cancer patients
           treated with EGFR tyrosine kinase inhibitor: Meta-analysis of 153 cohorts
           with 15,713 patients: Meta-analysis of incidence and risk factors of
           EGFR-TKI pneumonitis in NSCLC
    • Abstract: Publication date: Available online 24 September 2018Source: Lung CancerAuthor(s): Ran Xu, Jing Zhu
       
  • Characteristics, incidence, and risk factors of immune checkpoint
           
    • Abstract: Publication date: Available online 18 September 2018Source: Lung CancerAuthor(s): Jun Yeun Cho, Junghoon Kim, Jong Seok Lee, Yu Jung Kim, Se Hyun Kim, Yeon Joo Lee, Young-Jae Cho, Ho Il Yoon, Jae Ho Lee, Choon-Taek Lee, Jong Sun Park ObjectivesImmune checkpoint inhibitors (ICIs) can cause pneumonitis in lung cancer patients. We aimed to identify the clinical and radiologic characteristics, incidence, and risk factors of ICI-related pneumonitis in patients with non-small cell lung cancer (NSCLC).Materials and MethodsMedical records and chest computed tomography scans of NSCLC patients treated with an ICI over a 5-year period at a tertiary hospital were retrospectively analyzed. Clinical characteristics were compared between patients with and without ICI-related pneumonitis to identify risk factors.ResultsData from 167 eligible patients were analyzed. The incidences of all-grade and grade 3–4 pneumonitis were 13.2% and 4.2%, respectively. The presence of preexisting interstitial lung disease [odd ratio (OR), 6.03; 95% confidence interval (CI), 1.19–30.45; P = 0.030] was associated with a higher incidence of ICI-related pneumonitis. The presence of extrathoracic metastasis [OR, 0.34; 95% CI, 0.13–0.92; P = 0.034] was associated with a lower incidence of ICI-related pneumonitis. The dominant radiologic pattern (72.7%) of ICI-related pneumonitis was organizing pneumonia. Half of the patients with pneumonitis completely recovered or improved; however, the mortality rate was 18.2%.ConclusionICIs should be used with caution when treating lung cancer patients who have underlying chronic lung disease, especially interstitial lung disease.
       
  • Phase I/II study of carboplatin plus nab-paclitaxel and concurrent
           radiotherapy for patients with locally advanced non–small cell lung
           cancer
    • Abstract: Publication date: Available online 18 September 2018Source: Lung CancerAuthor(s): Yuko Kawano, Tomonari Sasaki, Hiroyuki Yamaguchi, Katsuya Hirano, Atsushi Horiike, Miyako Satouchi, Shinobu Hosokawa, Ryotaro Morinaga, Kazutoshi Komiya, Koji Inoue, Yuka Fujita, Ryo Toyozawa, Tomoki Kimura, Kosuke Takahashi, Kazuo Nishikawa, Junji Kishimoto, Yoichi Nakanishi, Isamu OkamotoABSTRACTObjectivesChemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC).Patients and MethodsIn a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL–1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation.ResultsIn the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2–85.9%), median progression-free survival was 11.8 months (60% CI, 10.6–16.2 months; 95% CI, 8.2–20.8 months), and median overall survival was not reached.ConclusionOur results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.
       
  • CT-based radiomics signature for differentiating solitary granulomatous
           nodules from solid lung adenocarcinoma
    • Abstract: Publication date: Available online 17 September 2018Source: Lung CancerAuthor(s): Xinguan Yang, Jianxing He, Jiao Wang, Weiwei Li, Chunbo Liu, Dashan Gao, Yubao Guan ObjectivesPulmonary granulomatous nodule (GN) with spiculated or lobulated appearance are indistinguishable from solid lung adenocarcinoma (SADC) based on CT morphological features, and partial false-positive findings on PET/CT. The objective of this study was to investigate the ability of quantitative CT radiomics for preoperatively differentiating solitary atypical GN from SADC.Methods302 eligible patients (SADC = 209, GN = 93) were evaluated in this retrospective study and were divided into training (n = 211) and validation cohorts (n = 91). Radiomics features were extracted from plain and vein-phase CT images. The L1 regularized logistic regression model was used to identify the optimal radiomics features for construction of a radiomics model in differentiate solitary GN from SADC. The performance of the constructed radiomics model was evaluated using the area under curve (AUC) of receiver operating characteristic curve (ROC).Results16.7% (35/209) of SADC were misdiagnosed as GN and 24.7% (23/93) of GN were misdiagnosed as lung cancer before surgery. The AUCs of combined radiomics and clinical risk factors were 0.935, 0.902, and 0.923 in the training cohort of plain radiomics(PR), vein radiomics, and plain and vein radiomics, and were 0.817, 0835, and 0.841 in the validation cohort of three models, respectively. PR combined with clinical risk factors (PRC) performed better than simple radiomics models (p 
       
  • Detection of autoantibodies against cancer-testis antigens in non-small
           cell lung cancer
    • Abstract: Publication date: Available online 17 September 2018Source: Lung CancerAuthor(s): Dijana Djureinovic, Tea Dodig-Crnkovic, Cecilia Hellström, Georg Holgersson, Michael Bergqvist, Johanna S.M Mattsson, Fredrik Pontén, Elisabeth Ståhle, Jochen M. Schwenk, Patrick Micke ObjectivesCancer-testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies.Materials and methodsTo comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases.ResultsAltogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against cancer-testis antigen family member 47, member A (CT47 A) genes, P antigen family 3 (PAGE3), variable charge X-linked (VCX), melanoma antigen family B 1 (MAGEB1), Lin-28 homolog B (LIN28B) and chromosome 12 open reading frame 54 (C12orf54) were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.ConclusionWe identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.
       
  • Prospective Study Revealed Prognostic Significance of Responses in
           Leptomeningeal Metastasis and Clinical Value of Cerebrospinal Fluid-based
           Liquid Biopsy
    • Abstract: Publication date: Available online 17 September 2018Source: Lung CancerAuthor(s): Yan Xu, Min Hu, Meizhuo Zhang, Wei Zhong, Xiaolu Yin, Yun Sun, Minjiang Chen, Jing Zhao, Xiaoyan Si, Hanping Wang, Xiaotong Zhang, Li Zhang, Ji Li, Hongzhi Guan, Zhenfan Yang, Mengzhao Wang ObjectiveLeptomeningeal metastasis (LM) secondary to non-small cell lung cancer (NSCLC) is a devastating complication associated with poor prognosis. Diagnosis and assessment of responses in LM have been challenging due to limitation of traditional imaging tools and lack of standard evaluation criteria until very recently. To bridge this gap, we conducted the first prospective, observational study in cytologically diagnosed NSCLC-LM patients (NCT02803619).Patients and methodsA total of 49 NSCLC-LM patients were enrolled. LM responses were evaluated with a composite endpoint integrating neurological symptoms, cerebrospinal fluid (CSF) parameters and central nervous system (CNS) imaging. Primary outcome was overall survival (OS) after diagnosis of LM. Exploratory endpoint was the association between OS and prognostic factors. Primary tumor and CSF samples were collected for biomarker analysis.Results93.9% of the cohort carried oncogenic drivers, and 85.7% harbored EGFR activating mutations. Median OS since LM diagnosis of the overall population was 9.7 months. EGFR mutant LM patients had a longer survival compared with wildtype ones. LM clinical responses assessed by the composite endpoint showed significant correlation with OS. Status of EGFR activating mutations was highly concordant between primary tumor and CSF. T790 M occurrence in CNS lesions was relatively rare and associated with intracranial exposure level of EGFR-TKIs.ConclusionOur results supported the composite endpoint for objective response evaluation of LM was valid, suggested LM outweighed peripheral lesions on the impact to patient survival, and emphasized the urge and promise of development of CNS-penetrant targeted therapies to improve clinical outcome of NSCLC-LM patients.
       
  • Detection of abundant megakaryocytes in pulmonary artery blood in lung
           cancer patients using a microfluidic platform
    • Abstract: Publication date: Available online 16 September 2018Source: Lung CancerAuthor(s): Hitoshi Dejima, Hayao Nakanishi, Hiroaki Kuroda, Mayumi Yoshimura, Noriaki Sakakura, Nanae Ueda, Yuko Ohta, Rie Tanaka, Sayomi Mori, Tatsuya Yoshida, Toyoaki Hida, Noriyoshi Sawabata, Yasushi Yatabe, Yukinori SakaoABSTRACTObjectivesThe lung was recently re-discovered as a hematopoietic organ for platelet production in mice. However, evidence for the role of the lung in thrombopoiesis in humans is still limited. In this study, we examined megakaryocytes in the pulmonary and systemic circulation, specifically in pulmonary arterial blood (PAB), venous blood (PVB) and peripheral blood using a newly developed microfluidic platform for rare cell isolation.Materials and methodsWe analyzed 23 lung cancer patients who underwent surgery in our institute. PAB and PVB were obtained from the resected lung immediately after surgery. Blood samples were size-selected using a filtration-based microfluidic device and enriched rare cells on glass slide specimens were stained with Papanicolaou (Pap), immunocytochemistry (ICC), and immunofluorescence (IF). Lung tissues were also analyzed by immunohistochemistry.ResultsPap/ICC/IF showed the presence of abundant CD61+/cytokeratin- giant cells with a megakaryocyte lineage in PAB, but only a few in PVB. These megakaryocytes were found to consist of CD61+/CD41+ immature megakaryocytes and CD61+/CD41- mature megakaryocytes with the potential to produce platelets. These findings were confirmed by the conventional hematological analysis of blood smears stained with Giemsa. In analysis of lung cancer, CD61+ megakaryocytes were observed exclusively in the capillaries of non-cancerous tissue, whereas platelets were selectively observed in the tumor blood vessels of cancerous tissue.ConclusionsThese results indicate that numerous megakaryocytes migrate from systemic bone marrows to accumulate in PAs and arrest of mature megakaryocytes in the capillaries of normal lung, suggesting the possibility that the lung plays a physiological role in the systemic thrombopoiesis in lung cancer patients.
       
  • Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in
           patients with EGFR-mutated and ALK-rearranged lung cancer
    • Abstract: Publication date: Available online 14 September 2018Source: Lung CancerAuthor(s): Si-yang Liu, Zhong-yi Dong, Si-pei Wu, Zhi Xie, Li-xu Yan, Yu-Fa Li, Hong-hong Yan, Jian Su, Jin-Ji Yang, Qing Zhou, Wen-Zhao Zhong, Hai-Yan Tu, Xue-Ning Yang, Xu-Chao Zhang, Yi-Long Wu ObjectivesEGFR-mutated or ALK-rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8 + T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS).Materials and MethodsTumor samples from 715 patients with lung cancer were retrospectively collected at Guangdong Lung Cancer Institute. Tumoral PD-L1 expression (N = 715) and CD8 + T cells infiltration (N = 658) was determined by immunohistochemistry (IHC), based on which TME was categorized into four different subtypes: PD-L1+/CD8+, PD-L1-/CD8+, PD-L1+/CD8-, PD-L1-/CD8-. Proportion of four TME subtypes was determined, and overall survival with PD-L1 expression and TME was analyzed.ResultsIn patients with EGFR mutations or ALK rearrangements, proportion of PD-L1+/CD8+ tumors was the lowest (5.0%, 17/342), and that of PD-L1-/CD8- tumors was the highest (63.5%, 217/342). In patients with wild-type EGFR and ALK, 14.2% (45/316) tumors were PD-L1+/CD8+ and 50.3% (159/316) tumors were PD-L1-/CD8- (P 
       
  • A multicenter, open-label, phase II trial of S-1 plus carboplatin in
           advanced non-small cell lung cancer patients with interstitial lung
           disease
    • Abstract: Publication date: Available online 12 September 2018Source: Lung CancerAuthor(s): Masaki Hanibuchi, Soji Kakiuchi, Shinji Atagi, Fumitaka Ogushi, Eiji Shimizu, Takashi Haku, Yuko Toyoda, Masahiko Azuma, Mayo Kondo, Hiroshi Kawano, Kenji Otsuka, Satoshi Sakaguchi, Hiroshi Nokihara, Hisatsugu Goto, Yasuhiko Nishioka ObjectivesThe clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD.Materials and MethodsA total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate.ResultsThe median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%).ConclusionThis is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046).
       
  • The Immune checkpoint, HVEM may contribute to immune escape in Non-Small
           Cell Lung Cancer lacking PD-L1 Expression
    • Abstract: Publication date: Available online 12 September 2018Source: Lung CancerAuthor(s): Shengxiang Ren, Qinrui Tian, Nadav Amar, Hui Yu, Christopher J. Rivard, Charles Caldwell, Terry L. Ng, Megan Tu, Yiwei Liu, Dexiang Gao, Kim Ellison, Kenichi Suda, Leslie Rozeboom, Gareth Rivalland, Paul Mitchell, Caicun Zhou, Fred R. Hirsch BackgroundHerpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.MethodsA TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.ResultsHVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p 
       
  • Examining the role of access to care: Racial/ethnic differences in receipt
           of resection for early-stage non-small cell lung cancer among integrated
           system members and non-members
    • Abstract: Publication date: Available online 11 September 2018Source: Lung CancerAuthor(s): Devon K. Check, Kathleen B. Albers, Kanti M. Uppal, Jennifer Marie Suga, Alyce S. Adams, Laurel A. Habel, Charles P. Quesenberry, Lori C. Sakoda ObjectivesTo examine the role of uniform access to care in reducing racial/ethnic disparities in receipt of resection for early stage non-small cell lung cancer (NSCLC) by comparing integrated health system member patients to demographically similar non-member patients.Materials and methodsUsing data from the California Cancer Registry, we conducted a retrospective cohort study of patients from four racial/ethnic groups (White, Black, Hispanic, Asian/Pacific Islander), aged 21 to 80, with a first primary diagnosis of stage I or II NSCLC between 2004 and 2011, in counties served by Kaiser Permanente Northern California (KPNC) at diagnosis. Our cohort included 1,565 KPNC member and 4,221 non-member patients. To examine the relationship between race/ethnicity and receipt of surgery stratified by KPNC membership, we used modified Poisson regression to calculate risk ratios (RR) adjusted for patient demographic and tumor characteristics.ResultsBlack patients were least likely to receive surgery regardless of access to integrated care (64-65% in both groups). The magnitude of the black-white difference in the likelihood of surgery receipt was similar for members (RR: 0.82, 95% CI: 0.73-0.93) and non-members (RR: 0.86, 95% CI: 0.80-0.94). Among members, roughly equal proportions of Hispanic and White patients received surgery; however, among non-members, Hispanic patients were less likely to receive surgery (non-members, RR: 0.93, 95% CI: 0.86-1.00; members, RR: 0.98, 95% CI: 0.89-1.08).ConclusionDisparities in surgical treatment for NSCLC were not reduced through integrated health system membership, suggesting that factors other than access to care (e.g., patient-provider communication) may underlie disparities. Future research should focus on identifying such modifiable factors.
       
  • MET amplification increases the metastatic spread of EGFR-mutated NSCLC
    • Abstract: Publication date: Available online 11 September 2018Source: Lung CancerAuthor(s): Simon Baldacci, Zoulika Kherrouche, Vincent Cockenpot, Luc Stoven, Marie Christine Copin, Elisabeth Werkmeister, Nathalie Marchand, Maéva Kyheng, David Tulasne, Alexis B. Cortot BackgroundFive to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) throughMET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown.MethodsWe investigated,in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression.ResultsMET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo, MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification.ConclusionMET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification.
       
  • Comment on: Erlotinib in combination with bevacizumab has potential
           benefit in non small cell lung cancer: A systematic review and
           meta-analysis of randomized clinical trials
    • Abstract: Publication date: Available online 7 September 2018Source: Lung CancerAuthor(s): Ran Xu, Jing Zhu
       
  • Different pattern of PD-L1, IDO, and FOXP3 Tregs expression with survival
           in thymoma and thymic carcinoma
    • Abstract: Publication date: Available online 7 September 2018Source: Lung CancerAuthor(s): Yu-Feng Wei, Chang-Yao Chu, Chao-Chun Chang, Sheng-Hsiang Lin, Wu-Chou Su, Yau-Lin Tseng, Chien-Chung Lin, Yi-Ting Yen ObjectivesThe expression of immune checkpoint ligand PD-L1 have been reported in various tumors. The expression of IDO and FOXP3 Tregs are considered to be associated with tumor-induced tolerance and poor outcome. Their prognostic role in surgically treated thymoma and thymic carcinoma, however, has not been investigated.Materials and MethodsTissue microarray (TMA) blocks comprised of 100 surgically treated thymomas and 69 surgically treated thymic carcinomas were conducted. Tissue sections were incubated with primary antibodies against PD-L1 (clone E1L3N, 1:100), IDO (clone 10.1, 1:50), and FOXP3 (clone 236 A/E7, 1:50). Comparisons for categorical variables were performed using χ2 test and Fisher’s exact test. Survival analysis were established using Kaplan-Meier method and log-rank test. Univariate and multivariate analyses were performed using Cox regression model.Results and ConclusionsHigh expression of PD-L1, IDO, and FOXP3 Tregs were identified in 36 (36%), 13 (13%), and 16 (16%) thymoma patients, respectively. High expression of PD-L1, IDO, and FOXP3 Tregs was associated with higher grade of tumor histology (P 
       
  • Predictive accuracy of lepidic growth subtypes in early-stage
           adenocarcinoma of the lung by quantitative CT histogram and FDG-PET
    • Abstract: Publication date: November 2018Source: Lung Cancer, Volume 125Author(s): Daisuke Eriguchi, Yoshihisa Shimada, Kentaro Imai, Hideyuki Furumoto, Tetsuya Okano, Ryuhei Masuno, Jun Matsubayashi, Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda ObjectivesThe aim of this study was to analyze the accuracy of computed tomography (CT) and F-18 fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to distinguish lepidic growth adenocarcinoma (LGA), including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma, all of which have favorable survival outcomes, from the more aggressive and invasive non-LGA subtypes.Materials and MethodsWe identified 225 patients with c-0/I adenocarcinoma of the lung who underwent PET/CT and 3DCT followed by complete resection. Maximum standardized uptake values (SUVmax) of FDG and several histogram parameters were analyzed. Histological grades were classified according to the predominant subtype (G1: lepidic; G3: micropapillary or solid; and G2: subtypes other than G1/G3).ResultsThe proportion of pathological invasive factors (lymphatic vessel involvement/blood vessel invasion/pleural invasion/lymph node metastasis) of patients with preinvasive adenocarcinoma, G1, G2, and G3 tumors were 0%, 3.6%, 48.0%, and 100%, respectively; p 
       
  • Three new disease-progression modes in NSCLC patients after EGFR-TKI
           treatment by next-generation sequencing analysis
    • Abstract: Publication date: Available online 1 September 2018Source: Lung CancerAuthor(s): Yuqing Wei, Kaikai Shen, Tangfeng Lv, Xianghai Wang, Chuling Li, Hang Fan, Yanling Lv, Hongbing Liu, Yong Song IntroductionMost non-small-cell lung cancer (NSCLC) patients who exhibit good clinical responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) will inevitably develop disease progression. Herein, through next-generation sequencing (NGS), we aimed to investigate three new disease-progression modes of NSCLC patients after EGFR-TKI treatment.Materials and MethodsPatients with sensitive EGFR-mutations who acquired resistance to EGFR-TKIs and whose tissues were subjected to post-progression NGS were enrolled. The clinical characteristics, progression-free survival (PFS), genomic alterations and expression of EGFR-mutations among the three disease-progression modes were retrospectively analyzed.Results and ConclusionThe sites of disease progression were as follows: primary foci in 19.5% (8/41) (Mode 1), metastatic foci in 31.7% (13/41) (Mode 2), and both primary and metastatic foci in 48.8% (20/41) (Mode 3). The median PFS in Mode 1 was 6 months (95% CI 1-8), which was significantly shorter than the 11 months (95% CI 8-14) in Mode 2 and the 10 months (95% CI 3-16) in Mode 3 (p = 0.0084). The expression of Del19 was significantly different among the three modes (p = 0.02). The numbers and species of mutant genes in Mode 3 were obviously greater than those in Modes 1 and 2, and no gene amplifications were observed in Mode 2. Mutations in the TP53 gene were the most frequent genetic alteration found in our study, and these accounted for 48.8% (20/41) of all alterations. TP53 mutations in Mode 1 were mainly in exons 6 and 8, while in Mode 2 and Mode 3, all mutations were located from exon 4 to exon 8. A significant benefit in PFS was observed in the metastatic foci progression mode and in the dual primary and metastatic foci progression mode rather than in the primary foci progression mode, which had significant value in the design of therapeutic strategies.
       
  • Impact of Serum Vascular Endothelial Growth Factor and Interleukin-6 on
           Treatment Response to Epidermal Growth Factor Receptor Tyrosine Kinase
           Inhibitors in Patients with Non-Small-Cell Lung Cancer
    • Abstract: Publication date: Available online 31 August 2018Source: Lung CancerAuthor(s): Yijun Jia, Xuefei Li, Chao Zhao, Tao Jiang, Sha Zhao, Limin Zhang, Xiaozhen Liu, Jinpeng Shi, Meng Qiao, Jiawei Luo, Sangtian Liu, Ruoshuang Han, Xiaoxia Chen, Caicun Zhou BackgroundAlthough EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC), responses vary within individuals. The current study aimed to investigate whether serum levels of several cytokines and their dynamic changes during TKI treatment could be used to predict the efficacy of EGFR-TKIs.Materials and methodsPre-treatment and one-month post-treatment serum levels of hepatocyte growth factor (HGF), interleukin-10 (IL-10), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interferon gamma (IFN-γ) and monocyte chemotactic protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay and U-plex biomarker group assays in patients with EGFR-mutant NSCLC received first-line EGFR-TKIs.ResultsPatients who had lower baseline serum levels of IL-6 had better object response rate (ORR) than those with high levels (74.2% vs 42.9%, p =  0.014). PFS was significantly longer in patients with low baseline level of IL-6 (19.57 vs. 13.73 months, p = 0.003) and in those with reduced serum VEGF and HGF levels after treatment (20.30 vs. 14.33 months, p = 0.009; 22.77 vs. 14.33 months, p =  0.002; respectively). Multivariate analyses showed that lower baseline serum IL-6 level was significantly associated with longer PFS (HR = 0.469, p =  0.022) and OS (HR = 0.181, p =  0.004). Reduction of serum VEGF and HGF levels after treatment was associated with significantly longer PFS (HR = 0.447, p =  0.017; HR = 0.365, p =  0.003; respectively). Lower pre-treatment serum VEGF level was associated with dramatically longer OS (HR = 0.277, p =  0.018).ConclusionsOur study suggested that serum levels of HGF, IL-6 and VEGF and its dynamic change during TKI treatment could be used to predict the efficacy of EGFR-TKIs treatment in patients with EGFR-mutant NSCLC.
       
  • Predicting survival following surgical resection of lung cancer using
           clinical and pathological variables: the development and validation of the
           LNC-PATH score
    • Abstract: Publication date: Available online 31 August 2018Source: Lung CancerAuthor(s): Haval Balata, Philip Foden, Tim Edwards, Anshuman Chaturvedi, Mohamed Elshafi, Alexander Tempowski, Benjamin Teng, Paul Whittemore, Kevin Blyth, Andrew Kidd, Deborah Ellames, Louise Ann Flint, Jonathan Robson, Elaine Teh, Robin Jones, Timothy Batchelor, Philip Crosbie, Richard Booton, Matthew Evison IntroductionThe aim of this study was to develop and validate a simple prognostic scoring system using readily available clinical and pathological variables that could stratify patients according to the risk of death following lung cancer resection. We hypothesized that by using additional pathological variables not accounted for by pathological stage alone coupled with markers of overall fitness a new prognostic tool could be developed.MethodsMultivariable logistic regression analysis of pathological and other clinical variables from patients undergoing surgical resection of non-small cell lung cancer (NSCLC) were used to determine factors independently associated with 2-year overall survival and so derive the scoring system. The model was then validated in an external multi-centre dataset.ResultsUsing multivariable logistic regression on a large dataset (n = 1,421) the ‘LNC-PATH’ (Lymphovascular invasion, N-stage, adjuvant Chemotherapy, Performance status, Age, T-stage, Histology) prognostic score was devised and then validated using an external dataset (n = 402). This can be used to risk stratify patients into low, moderate and high-risk groups with a statistically significant difference between the three groups in their survival distributions. 83.8% of patients in the low-risk group survived two years after surgery compared to 55.6% in the moderate-risk group and 26.2% in the high-risk group. The score was shown to perform moderately well with an Area Under the Receiver Operating Characteristic curve (AUROC) value of 0.76 (95% CI: 0.73-0.79) and 0.70 (95% CI: 0.64-0.76) in the derivation and validation cohorts respectively.DiscussionThe LNC-PATH score predicts 2-year overall survival after surgery for NSCLC. This may allow the development of risk stratified follow-up protocols in survivorship clinics which could be the subject of future prospective studies.
       
  • Probable hereditary familial overlap syndrome with multiple synchronous
           lung tumors
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): Andrés F. Cardona, Zyanya Lucia Zatarain-Barrón, Cladelis Rubio, Stella Martínez, Alejandro Ruiz-Patiño, Luisa Ricaurte, Adriana Serna, Rodolfo Barrios, Juan Carlos Garzón, Constanza Navarrete, Alberto Balaguera, Luis Corrales, Leonardo Rojas, Oscar Arrieta Here we report a case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDH1). The patient developed multiple synchronous primary lung adenocarcinomas related to Intra-Alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma. Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcinoma, one lepidic spread tumor and in the STAS area). Likewise, the broad genomic analysis was performed on archival tissue from the previous bone tumor. Lung tumors were found to harbor PIK3CA (invasive lesions) and a rare in-frame insertion of nucleotides in exon 19 of EGFR (lepidic tumor). STAS area showed KRAS and BRAF mutations in two different segments, and osteosarcoma tested positive for well known PIK3CA, KRAS and CDH1 alterations. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of germline TP53 and CDH1 mutations with concurrent somatic alterations that elucidate the basis of tumor heterogeneity.
       
  • Applicability of the Lung-molGPA Index in Non-Small Cell Lung Cancer
           Patients with Different Gene Alterations and Brain Metastases
    • Abstract: Publication date: Available online 30 August 2018Source: Lung CancerAuthor(s): Author: Kaiyan Chen, Xiaoqing Yu, Fanrong Zhang, Yanjun Xu, Peng Zhang, Zhiyu Huang, Yun Fan ObjectivesThe Lung-molGPA index is based on the original diagnosis-specific graded prognostic assessment (DS-GPA) and incorporates recently reported gene alteration data, predicting the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic values of both DS-GPA and Lung-molGPA remain undetermined, especially for patients with different molecular types.Materials and MethodsA total of 1,184 NSCLC patients with BM were analyzed for clinical factors and outcomes at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA was newly developed for NSCLC patients with gene variations.ResultsNSCLC patients in the present study had a median survival time of 14.0 months from BM diagnosis. Both the DS-GPA and Lung-molGPA models could effectively predict the outcomes of NSCLC patients with BM (P 
       
  • Economic analysis of osimertinib in previously untreated EGFR-mutant
           advanced non-small cell lung cancer in Canada
    • Abstract: Publication date: Available online 30 August 2018Source: Lung CancerAuthor(s): Doreen A. Ezeife, Veronica Kirk, Derek S. Chew, Nancy A. Nixon, Roy Lee, Lisa W. Le, Kelvin K.-W. Chan, Natasha B. Leighl IntroductionOsimertinib improves progression-free survival in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with marked intracranial response rates. However, its cost-effectiveness in a publically funded health care system has not been established. We assessed the cost-effectiveness of first-line osimertinib from the public payer perspective in the Canadian health care system.MethodsA Markov model was developed to project the outcomes and direct medical costs of initial treatment with osimertinib or current standard-of-care (SoC) EGFR TKIs, gefinitib or afatinib, in patients with previously untreated EGFR-mutant advanced NSCLC. Clinical and cost input estimates were informed from the available literature. Model outcomes included costs (in 2018 Canadian dollars), life years (LYs), quality-adjusted life-years (QALYs), and the cost utility of osimertinib compared to SoC EGFR TKI, or incremental cost per QALY gained.ResultsInitial treatment with osimertinib was associated with a gain of 0.79 QALY [95% confidence interval (CI), 0.74 to 0.83] at an incremental cost of $176,394 CAD (95% CI, 176,383 to 176,405) vs. SoC EGFR TKI (incremental cost-effectiveness ratio [ICER]: $223,133/QALY gained; 95%CI, 198,144 to 252,805). Osimertinib had a 0% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. Deterministic sensitivity analysis showed that the cost of osimertinib had the largest impact on ICER results.ConclusionAt the current marketed price, first-line osimertinib therapy in patients with advanced EGFR-mutant lung adenocarcinoma is not cost-effective in Canada. Reduction of osimertinib cost, for example by 25%, can significantly improve the cost-effectiveness profile.
       
  • Bcl-2 expression in circulating tumor cells (CTCs) of patients with small
           cell lung cancer (SCLC) receiving front-line treatment
    • Abstract: Publication date: Available online 27 August 2018Source: Lung CancerAuthor(s): Ippokratis Messaritakis, Michail Nikolaou, Eleni Politaki, Fillipos Koinis, Eleni Lagoudaki, Anastasios Koutsopoulos, Nefeli Georgoulia, Vassilis Georgoulias, Athanasios Kotsakis IntroductionTo investigate the presence of Bcl-2+CTCs in chemotherapy-naïve SCLC patients and their clinical relevance during front-line treatment.MethodsPeripheral blood was obtained from 66 consecutive-patients before chemotherapy administration, after one-cycle and at relapse. CTCs were detected by CellSearch and immunofluorescence using anti-Bcl-2, anti-M30, anti-cytokeratins(CK), anti-CD45 and anti-vimentin(Vim) antibodies.ResultsBefore treatment, CTCs were detected in 62.1% and 72.7% of patients using the CellSearch and immunofluorescence (Bcl-2+/CD45-), respectively. One-treatment cycle significantly decreased both CTCs’ detection rate(p 
       
  • Pembrolizumab and Platinum-Based Chemotherapy as First-Line Therapy for
           Advanced Non–Small-Cell Lung Cancer: Phase 1 Cohorts From the
           KEYNOTE-021 Study
    • Abstract: Publication date: Available online 25 August 2018Source: Lung CancerAuthor(s): Shirish M. Gadgeel, James P. Stevenson, Corey J. Langer, Leena Gandhi, Hossein Borghaei, Amita Patnaik, Liza C. Villaruz, Matthew Gubens, Ralph Hauke, James Chih-Hsin Yang, Lecia V. Sequist, Robert Bachman, Sanatan Saraf, Harry Raftopoulos, Vassiliki PapadimitrakopoulouABSTRACTObjectivesPlatinum-based chemotherapy for advanced non―small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (Clinicaltrials.gov, NCT02039674), we evaluated the combinations of platinum-doublet chemotherapy with the anti―programmed death 1 monocloncal antibody pembrolizumab.Materials and MethodsPatients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review.ResultsOverall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C.ConclusionPembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy.
       
  • Cost-effectiveness of pembrolizumab as first-line therapy for advanced
           non-small cell lung cancer
    • Abstract: Publication date: Available online 22 August 2018Source: Lung CancerAuthor(s): Mina Georgieva, Joao P. da Silveira Nogueira Lima, Pedro Aguiar, Gilberto de Lima Lopes, Benjamin Haaland BackgroundAnti-PD-1 immunotherapy has dramatically shifted therapeutic perspectives for advanced non-small cell lung cancer (NSCLC). We assessed cost-effectiveness of anti-PD-1 antibody pembrolizumab compared to platinum-doublet chemotherapy as first-line therapy for advanced NSCLC.MethodsWe retrieved survival, progression, and safety data comparing first-line pembrolizumab to platinum-doublets for advanced NSCLC patients with PD-L1 expression ≥50%, non-mutated EGFR, and non-translocated ALK, from KEYNOTE-024. Published United Kingdom (UK) and United States (US) costs informed incremental cost-effectiveness ratios (ICERs). Our analysis was based on a Bayesian Markov model of disease with full lifetime horizon. We estimated costs in USD and summarized effectiveness as quality-adjusted life-years (QALYs).ResultsPatients treated with pembrolizumab accumulated 1.80 QALYs (95% CrI 1.56-1.89), for moderate dependency between outcomes, compared to 1.06 QALYs (0.94-1.13) with chemotherapy. From a British National Health System (NHS) perspective, the ICER was $52k ($43k-$69k) per end-of-life (EoL) adjusted QALY gained, above the 42k USD threshold, while from a US cost perspective, the ICER was $49k ($40k-67k) per EoL adjusted QALY, below the hypothetical 100k USD threshold.ConclusionsEvidence suggests first-line pembrolizumab for NSCLC may be cost-effective in the US but not the UK, in spite of very similar ICER values in both countries.
       
  • Dose Escalation and Associated Predictors of Survival with Consolidative
           Thoracic Radiotherapy in Extensive Stage Small Cell Lung Cancer (SCLC): A
           National Cancer Database (NCDB) Propensity-Matched Analysis
    • Abstract: Publication date: Available online 20 August 2018Source: Lung CancerAuthor(s): Shaakir Hasan, Paul Renz, Andrew Turrisi, Athanasios Colonias, Gene Finley, Rodney E. Wegner PurposeRandomized studies have demonstrated a survival benefit for consolidative thoracic radiotherapy (TRT) in extensive stage (ES) small cell lung cancer (SCLC), however the radiation dose and optimal selection criteria are often debated.MethodsWe analyzed 3,280 stage IV SCLC treated with double-agent chemotherapy and TRT within the National Cancer Data Base (NCDB) and evaluated the differences in selection patterns and survival outcomes for patients who received at least 45 Gy of TRT and those who received
       
  • A phase II randomized trial of adjuvant chemotherapy with S-1 versus S-1
           plus cisplatin for completely resected pathological stage II/IIIA
           non-small cell lung cancer
    • Abstract: Publication date: Available online 19 August 2018Source: Lung CancerAuthor(s): Tatsuro Okamoto, Tokujiro Yano, Mototugu Shimokawa, Sadanori Takeo, Koji Yamazaki, Kenji Sugio, Mitsuhiro Takenoyama, Akira Nagashima, Shuichi Tsukamoto, Motoharu Hamatake, Hideki Yokoyama, Hitoshi Ueda, Akira Motohiro, Tetsuzo Tagawa, Fumihiro Shoji, Takuro Kometani, Genkichi Saito, Yasuro Fukuyama, Gouji Toyokawa, Atsushi Osoegawa ObjectivesPlatinum-based combination chemotherapy is the standard postoperative adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC). Oral S-1 therapy has good efficacy and relatively low toxicity for the treatment of advanced NSCLC. Therefore, we investigated whether long-term S-1 monotherapy is also useful as an adjuvant therapy after surgery in patients with NSCLC.Patients and methodsWe conducted a phase II randomized open-label multi-institutional study in patients with pathological stage II/IIIA NSCLC (7th TNM classification) who underwent complete resection from 2009 to 2013. The primary endpoint, the 2-year disease-free survival (DFS) rate, was evaluated using the Bayesian method. Eligible patients were randomly assigned to two arms: oral S-1 monotherapy (S-1 arm) and S-1 plus cisplatin combination therapy followed by S-1 (S-1 plus cisplatin arm) both for a total of 1 year.ResultsA total of 70 and 71 patients were enrolled in S-1 arm and S-1 plus cisplatin arm, respectively. The 2-year DFS rates were 52% (95% confidence interval [CI], 0.40–0.63) and 61% (95% CI, 0.48–0.70) for S-1 arm and S-1 plus cisplatin arm, respectively. Both arms met the primary endpoint. Neither DFS nor OS was significantly different between the arms (log-rank test: P =  0.1695 and P =  0.8684, respectively). The main G3/4 adverse events were loss of appetite and anemia (S-1 vs. S-1 plus cisplatin: 4.3% vs. 11.6% and 0% vs. 5.8%, respectively). The treatment completion rate did not differ between the two arms (S-1 vs. S-1 plus cisplatin: 45.7%, 95% CI, 41.9–66.3% vs. 43.5% 95% CI, 44.0–68.4%).ConclusionsLong-term adjuvant chemotherapy with S-1 was a feasible and promising treatment for patients with completely resected NSCLC, regardless of cisplatin addition. S-1 monotherapy should be investigated further, based on its low toxicity and practical convenience.
       
  • High-throughput sequencing reveals distinct genetic features and clinical
           implications of NSCLC with de novo and acquired EGFR T790M mutation
    • Abstract: Publication date: Available online 15 August 2018Source: Lung CancerAuthor(s): Panwen Tian, Ye Wang, Weiya Wang, Yalun Li, Ke Wang, Xiaowei Cheng, Yuan Tang, Han Han-Zhang, Junyi Ye, Shannon Chuai, Weimin Li IntroductionDe novo T790 M mutation in EGFR has been reported in various studies. However, its genetic characteristics and association with EGFR tyrosine kinase inhibitors (TKIs) treatment responsiveness remain poorly studied.MethodsWe retrospectively screened 1228 consecutive non-small cell lung cancer (NSCLC) patients and identified 29de novo T790 M carriers. Capture-based targeted deep sequencing was conducted on 21 eligible samples as well as a 20-sample cohort with acquired T790 M mutation after EGFR-TKIs treatment. We characterized and compared their mutational profiles on 168 cancer-related genes.ResultsDe novo T790 M mutation was found in 5.8% of the TKI-naive patients harboring EGFR activating mutations. Among the de novo T790 M samples, T790 M was significantly more likely to coexist with L858R than with 19del (76.2% vs. 23.8%) compared to the acquired T790 M cohort (30.0% vs. 70.0%) (p = 0.003). These two groups harbored different mutant cancer-related genes as well. Notably, the ratio of allelic frequency (AF) of the T790 M mutation to the EGFR activating mutation in each patient, defined as the relative AF (RAF), differs significantly between the de novo and acquired T790 M cohorts (86.1% vs. 22.3%, p 
       
  • Intratumoral heterogeneity of copy number variation in lung cancer
           harboring L858R via immunohistochemical heterogeneous staining
    • Abstract: Publication date: Available online 13 August 2018Source: Lung CancerAuthor(s): Takafumi Hashimoto, Atsushi Osoegawa, Yohei Takumi, Miyuki Abe, Ryoji Kobayashi, Michiyo Miyawaki, Hideya Takeuchi, Tatsuro Okamoto, Kenji Sugio BackgroundAlthough intratumoral heterogeneity is commonly observed in several cancers, few studies have shown its presence in EGFR-mutated lung cancer. We performed immunohistochemistry to analyze the intratumoral heterogeneity in EGFR-mutated (L858R) lung cancer and performed targeted sequencing in specific cases. We discuss the effects of intratumoral heterogeneity and acquired resistance to EGFR-TKI.MethodsTwenty resected primary lung cancers known to harbor EGFR L858R were analyzed. IHC was performed using an L858R mutant-specific rabbit monoclonal antibody and the samples were scored by staining intensity (0-3) and proportion. For cases with heterogeneous L858R protein expression, the nucleic acids were extracted from each differently stained lesion, and targeted sequencing was performed. Single nucleotide variations (SNVs) and copy number variations (CNVs) were then analyzed. The cell proliferation and apoptosis were also evaluated by the ki-67 labeling index and TUNEL staining.ResultsAmong 20 cases, 3 showed heterogeneous staining. Genetic analyses for cases with heterogeneous staining revealed an increase in the copy number of EGFR in the IHC-positive part compared to the negative part, and an increase in the copy number of CCNE1 was observed in the IHC-positive part compared to the negative part in one case (case 1). In another case (case 2), an increase in the copy number of EGFR was observed in the IHC-positive part compared to the negative part, and an increase in the copy number of MDM2 was observed in the IHC-positive part compared to the negative part. In three cases, no SNV changes were observed. An increase in the ki-67 labeling index in the L858R-positive part in case 1 and increased apoptosis in the L858R-positive part in case 2 were observed, suggesting the functional significance of CNV changes.ConclusionThese cases exhibiting L858R IHC intratumoral heterogeneity suggest a heterogeneous effect on the cell activity due to CNV heterogeneity.
       
  • High UDG and BRCA1 Expression is Associated with Adverse Outcome in
           Patients with Pemetrexed Treated Non-Small Cell Lung Cancer
    • Abstract: Publication date: Available online 13 August 2018Source: Lung CancerAuthor(s): Nooshin Hashemi Sadraei, Yan Feng, Lingling Du, Pingfu Fu, Sulsal Haque, Afshin Dowlati, Jahnavi Gollamudi, Nathan A. Pennell, Tarek Mekhail, Stefanie Avril, Carol Farver, Stanton L. Gerson, Neelesh SharmaABSTRACTObjectiveThe antifolate chemotherapy agent pemetrexed has been widely used to treat non-small-cell-lung-cancer (NSCLC), but there is no clinically validated biomarker to select patients likely to respond. The aim of this study was to assess two proteins involved in DNA repair mechanisms, uracil DNA glycosylase (UDG) and BRCA1 as potential prognostic biomarkers in NSCLC patients treated with pemetrexed-based chemotherapy.Material and MethodsFormalin-fixed-paraffin-embedded tumor specimens from 119 patients with advanced NSCLC treated with pemetrexed between 2004 and 2011 were retrospectively analyzed. Expression of UDG, BRCA1, and known prognostic factors ALK, TTF-1, thymidylate synthase and folylpolyglutamate synthase was assessed by immunohistochemistry using H-SCORE (product of percent stained cells and intensity of expression). Progression-free (PFS) and overall survival (OS) served as reference endpoint.ResultsMost NSCLC tumor samples had UDG positivity in at least 5% of tumor cells and 34% samples had more than 50% positive tumor cells. Using the median expression value as threshold, high UDG expression (H-SCORE≥75) was significantly associated with shorter median PFS (3-year PFS 7% vs. 37%, p = 0.045) and a trend for shorter OS (3-year OS 15% vs 42%, p = 0.066) compared to patients with low UDG. In multivariable Cox analysis, the association between high UDG and shorter PFS was close to statistically significant (p = 0.08) at a significance level of 0.05 after controlling for age, gender, ALK- and TTF1-status with hazard ratio of 2.1. Grouping patients according to combined UDG and BRCA1 expression, patients with a profile of UDGhigh/BRCA1high had the shortest PFS and OS compared to all other patient groups (p = 0.007 and 0.02, respectively).ConclusionOur results demonstrate an important prognostic role for high UDG expression in pemetrexed-treated NSCLC patients, in addition to its previously reported role in pemetrexed cytotoxicity. High UDG expression was predictive of shorter PFS and OS, and patients with a combined profile of UDGhigh/BRCA1high had the poorest outcome following pemetrexed treatment.
       
  • Establishment of a platform of non-small-cell lung cancer patient-derived
           xenografts with clinical and genomic annotation
    • Abstract: Publication date: Available online 11 August 2018Source: Lung CancerAuthor(s): Han Na Kang, Jae Woo Choi, Hyo Sup Shim, Jinna Kim, Dae Joon Kim, Chang Young Lee, Min Hee Hong, Seong Yong Park, A-Young Park, Eun Joo Shin, Seo Yoon Lee, Kyoung-Ho Pyo, Mi Ran Yun, Hun Mi Choi, Sung Sook Lee, Seok-Young Kim, Hanna Lee, Soonmyung Paik, Byoung Chul Cho, Jin Gu Lee BackgroundPreclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy.MethodsPatient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation. Established PDXs were examined by light microscopy, genomic profiling, and in vivo drug testing, and the successful engraft rate was analyzed with the mutation profile, histology, or acquisition method. Finally, the drug responses of PDXs were compared with the clinical responses of the respective patients.ResultsUsing samples from 122 patients, we established 41 NSCLC PDXs [30 adenocarcinoma (AD), 11 squamous cell carcinoma (SQ)], among which the following driver mutation were observed: 13 EGFR-mutant, 4 ALK-rearrangement, 1 ROS1-rearrangement, 1 PIK3CA-mutant, 1 FGFR1-amplification, and 2 KRAS-mutant. We rigorously characterized the relationship of clinical features to engraftment rate and latency rates. The engraft rates were comparable across histologic type. The AD engraft rate tended to be higher for surgically resected tissues relative to biopsies, whereas similar engraft rates was observed for SQ, irrespective of the acquisition method. Notably, EGFR-mutants demonstrated significantly longer latency time than EGFR-WT (86 vs. 37days, P = 0.007). The clinical responses were recapitulated by PDXs harboring driver gene alteration (EGFR, ALK, ROS1, or FGFR1) which regressed to their target inhibitors, suggesting that established PDXs comprise a clinically relevant platform.ConclusionThe establishment of genetically and clinically annotated NSCLC PDXs can yield a robust preclinical tool for biomarker, therapeutic target, and drug discovery.
       
  • Non-invasive detection of actionable mutations in advanced non-small-cell
           lung cancer using targeted sequencing of circulating tumor DNA
    • Abstract: Publication date: Available online 8 August 2018Source: Lung CancerAuthor(s): Wey Cheng Sim, Chet Hong Loh, Xian Toh Li, Chia Wei Lim, Akhil Chopra, Alex Yuan Chi Chang, Liuh Ling Goh ObjectiveTo evaluate the feasibility of detecting actionable gene mutations in circulating tumor DNA (ctDNA) in patients with advanced non-small-cell lung cancer (NSCLC) using targeted next-generation sequencing (NGS).Materials and methodsIn total 50 plasma samples from patients newly diagnosed with advanced NSCLC or resistant to first-line tyrosine kinase inhibitors (TKIs) were subjected to deep sequencing on a seven-gene panel (BRAF, EGFR, ERBB2, KRAS, NRAS, PIK3CA, PTEN) incorporated with molecular barcodes to improve accuracy in variant detection. When possible, results were compared with those from matched tissue samples.ResultsAt least one alteration in the ctDNA was detected in 44 out of 50 patients (88%); EGFR was the most frequently mutated gene. Half the total number of patients (50%, 25 of 50) had at least one actionable genetic alteration with targeted therapies available for treatment. Our results showed a high concordance rate of 81% in detection of EGFR mutation between 26 matched tissue and plasma samples. For progressive patients, from whom tissue is mostly unavailable, the resistant EGFR T790 M mutation was validated using the droplet digital polymerase chain reaction (ddPCR), yielding a concordance of 92% between alternative platforms.ConclusionOur study demonstrated that therapeutically actionable mutations can be detected with high accuracy in ctDNA using NGS. This promising approach offers alternative and non-invasive diagnostic methods for treatment guidance and clinical monitoring.
       
  • Targeted lung cancer screening selects individuals at high risk of
           cardiovascular disease
    • Abstract: Publication date: Available online 8 August 2018Source: Lung CancerAuthor(s): H Balata, S Blandin Knight, P Barber, D Colligan, EJ Crosbie, R Duerdan, P Elton, M Evison, M Greavesd, J Howells, K Irion, D Karunaratne, M Kirwan, A Macnab, S Mellor, C Miller, T Newton, J Novasio, R Sawyer, A Sharman BackgroundCardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention.MethodsThe Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55-74 and 6-year risk ≥1.51%, using PLCOM2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score.ResultsSeventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCOM2012) scores were correlated (r = 0.26, p 
       
  • Multisite stereotactic body radiotherapy for metastatic non-small-cell
           lung cancer: delaying the need to start or change systemic therapy'
    • Abstract: Publication date: Available online 7 August 2018Source: Lung CancerAuthor(s): Tomas Merino Lara, Joelle Helou, Ian Poon, Arjun Sahgal, Hans T. Chung, William Chu, Hany Soliman, Yee Ung, Sunil Verma, Parneet Cheema, Susanna Cheng, Suneil Khanna, Darby Erler, Liying Zhang, Patrick Cheung ObjectivesThe purpose of this study was to review the clinical outcomes following the use of stereotactic body radiotherapy (SBRT) in patients with metastatic non-small-cell lung cancer (NSCLC) from a large academic institution.Materials and methods: Metastatic NSCLC patients treated with extracranial SBRT were identified from an institutional database. Treatment indications were: (1) oligometastases, (2) oligoprogression, and (3) local control of dominant tumors. Endpoints included overall survival (OS), progression-free survival (PFS), time to starting/changing systemic therapy (SCST), and local failure (LF). Univariate and multivariable analyses were performed to look for predictive factors.Results108 patients with 165 tumors were treated. SBRT was delivered for oligometastases in 66 patents, for oligoprogression in 20 patients, and for local control in 22 patients. Median OS and PFS for all patients were 27.3 months and 4.4 months, respectively, with treatment indication being the only predictive factor on multivariable analysis (patients with oligometastases having the highest median OS and PFS of 39.3 months and 7.6 months respectively). Cumulative incidence of SCST was only 21.5% at 1 year after SBRT, with larger tumor size and positivity for EGFR/ALK mutation being predictive of higher rates of SCST on multivariable analysis. LF was 15.6% at 1 year, with larger tumor size and exposure to previous systemic therapy being predictive of higher rates of LF on multivariable analysis.ConclusionPatients treated with SBRT for oligometastases have better OS and PFS than those treated for oligoprogression or for local control of dominant tumors. Use of SBRT may delay the need for SCST. Larger tumors and previous exposure to systemic therapy were predictive of higher rates of LF.
       
  • Cost-effectiveness of a low-dose computed tomography screening programme
           for lung cancer in New Zealand
    • Abstract: Publication date: Available online 6 August 2018Source: Lung CancerAuthor(s): Richard Jaine, Giorgi Kvizhinadze, Nisha Nair, Tony Blakely ObjectivesThe cost-effectiveness of low-dose computed tomography (LDCT) screening for lung cancer is uncertain. This study estimated the health gains, costs (net health system, and including ‘unrelated’) and cost-effectiveness of biennial LDCT screening among 55-74 years olds with a smoking history of at least 30 pack years, and (if a former smoker) having quit within last 15 years, in New Zealand.MethodsWe used a macrosimulation stage shift model with New Zealand-specific lung cancer incidence rates and intervention parameters from the National Lung Screening Trial, a health system perspective, and a lifetime horizon for quality-adjusted life-years (QALYs) and costs discounted at 3% per annum. We also examined heterogeneity by gender, ethnicity (Māori (indigenous population) versus non-Māori), age and current versus ex-smoking status.Results and ConclusionWe estimated 0.037 QALYs gained (95% uncertainty interval (UI) 0.024 to 0.053) per eligible participant, at a cost of US$3606 ($2689-4681). The overall incremental cost effectiveness ratio (ICER) was US$104,000 per QALY gained (95% UI US$59,000 to US$175,000).The cost-effectiveness varied moderately by socio-demographics, with the ‘best’ ICER being US$52,000 for 70-74 year old Māori females and the ‘worst’ ICER being US$142,000 for 55-59 year old non-Māori females. The ICER varied little by current smoking status, due to higher competing mortality risk limiting QALY gains for current smokers.The two scenarios that lowered the ICER the most were increasing the screening uptake to 100% (ICER = US$50,000 per QALY), and improving the sensitivity (from 93.8% to 98%) and specificity (from 73.4% to 95%) of the screening test (ICER = US$42,000 per QALY).Based on a threshold of GDP per capita per QALY gained (i.e. US$30,000), LDCT screening for lung cancer is unlikely to be cost-effective in New Zealand for any sociodemographic group.
       
  • Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC):
           outcomes with immune check-point inhibitors (ICPi)
    • Abstract: Publication date: Available online 3 August 2018Source: Lung CancerAuthor(s): Elizabeth Dudnik, Elias Bshara, Ahuva Grubstein, Ludmila Fridel, Tzippy Shochat, Laila C. Roisman, Maya Ilouze, Anna Belilovski Rosenblum, Smadar Geva, Alona Zer, Ofer Rotem, Aaron M. Allen, Nir Peled ObjectivesEfficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown.Materials and MethodsConsecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278).ResultsOf 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1-49% and  0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9-44.9) and 13 months (95% CI, 6.6-15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1).ConclusionIn NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.
       
  • Lung cancer CT screening: psychological responses in the presence and
           absence of pulmonary nodules
    • Abstract: Publication date: Available online 3 August 2018Source: Lung CancerAuthor(s): Marcia E Clark, Laura E Bedford, Ben Young, John FR Robertson, Roshan das Nair, Kavita Vedhara, Roberta Littleford, Francis M Sullivan, Frances S Mair, Stuart Schembri, Petra Rauchhaus, Denise Kendrick ObjectivesTo determine the psychological response (thoughts, perceptions and affect) to a diagnosis of pulmonary nodules following a novel antibody blood test and computed tomography (CT) scans within a UK population.Materials and methodsThis study was nested within a randomised controlled trial of a blood test (Early CDT®-Lung test), followed by a chest x-ray and serial CT-scanning of those with a positive blood test for early detection of lung cancer (ECLS Study). Trial participants with a positive Early CDT®-Lung test were invited to participate (n = 338) and those agreeing completed questionnaires assessing psychological outcomes at 1, 3 and 6 months following trial recruitment. Responses of individuals with pulmonary nodules on their first CT scan were compared to those without (classified as normal CT) at 3 and 6 months follow-up using random effects regression models to account for multiple observations per participant, with loge transformation of data where modelling assumptions were not met.ResultsThere were no statistically significant differences between the nodule and normal CT groups in affect, lung cancer worry, health anxiety, illness perceptions, lung cancer risk perception or intrusive thoughts at 3 or 6 months post-recruitment. The nodule group had statistically significantly fewer avoidance symptoms compared to the normal CT group at 3 months (impact of events scale avoidance (IES-A) difference between means -1.99, 95%CI -4.18, 0.21) than at 6 months (IES-A difference between means 0.88, 95%CI -1.32, 3.08; p-value for change over time = 0.003) with similar findings using loge transformed data.ConclusionA diagnosis of pulmonary nodules following an Early CDT®-Lung test and CT scan did not appear to result in adverse psychological responses compared to those with a normal CT scan.
       
  • Carving Out Another Slice of the Pie: Exceptional Response to Single Agent
           Imatinib in an Asian Female Never-smoker with Advanced NSCLC and a De-novo
           PDGFR-α N848 K Mutation
    • Abstract: Publication date: Available online 31 July 2018Source: Lung CancerAuthor(s): Samuel J. Klempner, Kyle Gowen, Thomas K. Lee, Viola W. Zhu, Alexa B. Schrock, Vincent A. Miller, Siraj M. Ali, Sai-Hong Ignatius Ou Non-small cell lung cancer (NSCLC) has emerged as a paradigm for clinical application of precision medicine as optimal therapy is commonly chosen based on genomic biomarkers identified in a patient’s tumor sample. Recurrent driver alterations are well described, however, a need to continually identify rare variants remains clinically relevant. We identified an incident case of advanced NSCLC with a PDGFR-α N848 K activation loop mutation with no other concurrent oncogenic drivers. Amino acid sequence alignment confirmed homology to the imatinib-sensitive KIT N822 K activation loop mutation observed in GIST. The patient achieved a 2-year response to single agent imatinib that is ongoing. While PDGFRA N848 K is rare among public sequencing databases our cases strongly suggests functional relevance and highlights the importance of studying rare variants in NSCLC.
       
  • Automated chromogenic multiplexed immunohistochemistry assay for diagnosis
           and predictive biomarker testing in non-small cell lung cancer
    • Abstract: Publication date: Available online 31 July 2018Source: Lung CancerAuthor(s): Marius Ilie, Mélanie Beaulande, Marame Hamila, Gilles Erb, Véronique Hofman, Paul HofmanABSTRACTObjectivesThe current challenge in the management of non-small cell lung cancer (NSCLC) in pathology laboratories is to combine immunohistochemistry (IHC) and molecular approaches on increasingly smaller biopsies and the need to reserve a fair amount of tumor material for molecular analyses with increasingly larger panels. The latest lung cancer classification, especially in the setting of poorly differentiated tumors, requires an IHC workup to allow for accurate diagnosis and also to preserve as much tissue as possible for molecular testing. Thus, it is recommended to reduce use of the term NSCLC not otherwise specified as much as possible and classify tumors according to their specific histologic subtype. This implies limiting the number of tissue slides despite the existence of specific and sensitive biomarkers (ALK, ROS1, BRAF V600E, PD-L1) and the obligation to distinguish lung adenocarcinoma (TTF-1 positive) from squamous cell carcinoma (p40 positive).Materials and MethodsSamples from 18 patients with NSCLC, previously characterized for histologic and genomic/immune features, were included. Two multiplexed IHC assays were developed, for diagnosis and immunophenotyping including TTF1, p40, PD-L1, and pan-Keratin antibodies, and for molecular profiling panel including ALK, ROS1 and BRAF V600E antibodies.ResultsWe developed two sensitive multiplexed IHC assays to comprehensively characterize major NSCLC histotypes and FDA-cleared predictive biomarkers, without antigenicity loss, steric interference or increased cross-reactivity. The assays rely on standard antigen retrieval and automated staining protocols, limiting the need for validation strategies.ConclusionOur multiplexed IHC approach provides a unique sample-sparing tool to characterize limited tissue samples in lung oncology and making it an alternative method in the clinical setting for therapeutic decision making of advanced NSCLC, provided that validation in a larger population is performed.
       
  • Crizotinib treatment for patients with EGFR mutation positive NSCLC that
           acquire cMET amplification after EGFR TKI therapy results in short-lived
           and heterogeneous responses
    • Abstract: Publication date: Available online 30 July 2018Source: Lung CancerAuthor(s): Bianca van Veggel, Adrianus J. de Langen, Sayed Hashemi, Kim Monkhorst, Efraim H. Rosenberg, Daniëlle A.M. Heideman, Teodora Radonic, Egbert F. Smit PurposeNext to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms. Here, we report on the clinical outcome of a series of patients with cMET-driven resistance to EGFR TKIs, treated with crizotinib.Materials and methodsEight patients with EGFR mutation positive NSCLC that acquired cMET amplification after EGFR TKI treatment were treated with crizotinib 250 mg twice daily, as monotherapy (n = 2) or in combination with an EGFR TKI (n = 6).ResultsFour out of eight patients (50%) showed a partial response (PR) according to RECIST 1.1. Median progression-free survival (PFS) was 1.4 (95% CI 1.2 – 5.0) months. Responses were short-lasting with a median PFS of 3.5 (95% CI 1.4 – 5.2) months in patients with a PR. Median overall survival was 5.9 (95% CI 1.3 – 6.0) months and not statistically different between responders and non-responders (p = 0.37). All but one patient tolerated crizotinib treatment well. Heterogeneous responses were seen in patients with progressive disease as best response with a marked size decrease of the biopsied (cMET amplification positive) lesion and progression of other lesions. cMET amplification was not always mutually exclusive with other EGFR TKI resistance mechanisms. Post-progression biopsies were negative for cMET amplification.ConclusionCrizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI treatment results in short-lived and often heterogeneous responses, possibly due to subclonality of cMET-driven resistance and co-occurrence of other EGFR TKI resistance mechanisms.
       
  • Highlights of the 14th International Mesothelioma Interest Group Meeting:
           Pathologic Separation of Benign from Malignant Mesothelial Proliferations
           and Histologic/Molecular Analysis of Malignant Mesothelioma Subtypes
    • Abstract: Publication date: Available online 30 July 2018Source: Lung CancerAuthor(s): Andrew Churg, Kazuki Nabeshima, Greta Ali, Rossella Bruno, Lynnette Fernandez-Cuesta, Francoise Galateau-Salle ObjectivesThe separation of benign from malignant mesothelial proliferations and exact subclassification of mesothelioma subtypes is crucial to determining patient care and prognosis but morphologically can be very difficult.MethodsThis session of the 2018 IMIG meeting addressed these problems.ResultsA new immunohistochemical marker, methylthioadenosine phosphorylase, was shown to correlate well with CDKN2 A FISH and is cheaper and faster to run. A 117 gene expression panel also provided good separation on both tissue biopsy and cytology samples. Review of a series of mesotheliomas thought to be biphasic produced only a moderate level of agreement among expert pathologists with some cases being classified as purely epithelioid or sarcomatoid; these classifications had prognostic significance. The entity called transitional mesothelioma was found to behave exactly like sarcomatoid mesothelioma. RNA-seq analysis of a large series of mesotheliomas from a public database showed that, genetically, the morphologic breakdown into epithelioid, sarcomatoid, or biphasic mesotheliomas is artificial because there is a continuous spectrum of genomic changes. There are now criteria for the diagnosis of mesothelioma in situ and this is potentially important, since such cases might be curable.ConclusionsThis session documented new morphological and molecular approaches to separating benign from malignant mesothelial proliferations and to subclassifying malignant mesoteheliomas in clinical relevant ways.
       
  • Exosomal RNA-profiling of pleural effusions identifies adenocarcinoma
           patients through elevated miR-200 and LCN2 expression
    • Abstract: Publication date: October 2018Source: Lung Cancer, Volume 124Author(s): Per Hydbring, Luigi De Petris, Yanming Zhang, Eva Brandén, Hirsh Koyi, Metka Novak, Lena Kanter, Petra Hååg, James Hurley, Vasisht Tadigotla, Baoli Zhu, Johan Skog, Kristina Viktorsson, Simon Ekman, Rolf Lewensohn HypothesisThe inherent challenges associated with tissue biopsies from lung have spurred an interest in the use of liquid biopsies. Pleural effusions are one source of liquid biopsy. Recently, extracellular vesicles of endocytic origin, exosomes, have attracted interest as liquid biopsy of tumors as they are thought to be a mirror of their tumor of origin. Here, we aimed to analyze if RNA profiling of exosomes isolated from pleural effusions could differentiate patients with lung adenocarcinoma from patients with benign inflammatory processes.MethodsExosomes were isolated from 36 pleural effusions from patients with adenocarcinoma (n = 18) and patients with benign inflammatory processes (n = 18). The two groups were balanced with respect to age and smoking history but with a gender bias towards males in the benign group. Profiling was conducted using RT-qPCR arrays covering 754 microRNAs and 624 mRNAs followed by statistical ranking of differentially regulated transcripts between the two patient cohorts.ResultsRNA profiling revealed differential expression of 17 microRNAs and 71 mRNAs in pleural effusions collected from patients with lung adenocarcinoma compared to pleural effusions from benign lung disease. Overall, top differentially expressed microRNAs, including miR-200 family microRNAs, provided a stronger diagnostic power compared to top differentially expressed mRNAs. However, the mRNA transcript encoding Lipocalin-2 (LCN2) displayed the strongest diagnostic power of all analyzed transcripts (AUC: 0.9916).ConclusionsOur study demonstrates that exosomal RNA profiling from pleural effusions can be used to identify patients with lung adenocarcinoma from individuals with benign processes and further proposes miR-200 microRNAs and LCN2 as diagnostic markers in lung cancer liquid biopsies.
       
  • Mechanisms of Primary Resistance to EGFR targeted therapy in
           advanced lung adenocarcinomas
    • Abstract: Publication date: Available online 29 July 2018Source: Lung CancerAuthor(s): Ying Jin, Xun Shi, Jun Zhao, Qiong He, Ming Chen, Junrong Yan, Qiuxiang Ou, Xue Wu, Yang W. Shao, Xinmin Yu IntroductionIncreasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma with EGFR mutations may impact clinical responses and outcomes to EGFR tyrosine kinase inhibitor (TKI) treatments.MethodsWe performed genetic profiling of pre-treatment samples of 69 lung adenocarcinoma patients, including tumor FFPE and cell-free DNA (cfDNA), targeting 416 cancer-related genes using next generation sequencing. We analyzed mutation concordance across sample types and investigated potential mechanisms that confer primary resistance to EGFR-TKIs in patients with short progression-free survival (PFS) versus those with long PFS.ResultsWe detected a total of 200 actionable genetic alterations (mean: 2.9 variants/patient, range: 1-7 variants) in tumor FFPE and 140 actionable genetic alterations (mean: 2.0 variants/patient, range: 0-5 variants) in matched cfDNA, respectively. All patients had EGFR TKI-sensitizing mutations, including EGFR Ex19del, L858R, G719S/C, and L861Q. Concurrent TP53 mutations were most commonly observed in 72.5% of patients, followed by EGFR amplification (20.3%), RB1 (10.1%), PIK3CA (7.2%), and MYC (5.8%). For EGFR activating mutations, the concordance rate was 88.2% between cfDNA and FFPE samples. Furthermore, we identified genes that potentially confer primary resistance to EGFR-TKIs including CDC73, SMAD4, RB1 and PIK3CA. We also report signaling pathways enriched in patients with TKI primary resistance.ConclusionsWe note the genetic complexity and heterogeneity of EGFR-mutated lung adenocarcinoma and underscore that mutation status is highly concordant between tumor FFPE and cfDNA samples. This study also highlights the alterations that potentially confer primary resistance to EGFR TKI treatments in patients who demonstrated short PFS.
       
  • A new bronchoscopic catheter for the transbronchial ablation of pulmonary
           nodules
    • Abstract: Publication date: Available online 26 July 2018Source: Lung CancerAuthor(s): Seyer Safi, Jan op den Winkel, Steve Kramer, Thomas Keast, Henky Wibowo, Thomas Muley, Felix J.F. Herth ObjectivesWith the objective of simultaneous bronchoscopic biopsy and ablation of malignant solitary pulmonary nodules, we have developed a flexible monopolar radiofrequency (RF) catheter that can be deployed through the working channel of most bronchoscopes. Herein, we present the results of a benchtop study demonstrating the local control of ablation achieved using this RF device.Materials and MethodsFresh tumor specimens were heated in a water bath to 37 °C, and the RF catheter was inserted into the tumors within the specimen. Temperature sensors were positioned 3 mm, 5 mm and 7 mm from the electrode to measure the temperature of the surrounding tissue every 1 second. The ablation was conducted by applying RF energy for 8 minutes. The ablated specimens were evaluated by cutting the tissue samples along the top of the device and measuring the ablation zones.ResultsFive ablations were performed in 3 specimens. All of the ablation zones had a major axis length (along the electrode axis) between 18.9 mm and 22.8 mm and a minor axis length (perpendicular to the major axis) between 13.3 mm and 18.0 mm. The temperature data showed that all of the temperature sensors detected 60 °C or higher. These results demonstrate that the RF catheter was capable of generating ablation zones that were locally contained in ex vivo human cancerous lung specimens and that incorporated the tumor tissues.ConclusionThis study suggests that the ex vivo ablation of lung malignancy with a new bronchoscopic RF catheter is feasible and that in vivo tumor ablation with this method in humans merits further study.
       
  • Cost-Utility Analysis of a Potential Lung Cancer Screening Program for a
           High-Risk Population in Germany: A Modelling Approach
    • Abstract: Publication date: Available online 24 July 2018Source: Lung CancerAuthor(s): Florian Hofer, Hans-Ulrich Kauczor, Tom Stargardt BackgroundLung cancer is the leading cause of cancer death in Germany. Although several randomized trials in Europe have evaluated the effectiveness of lung cancer screening programs, evidence on the cost-effectiveness of lung cancer screening is scarce.ObjectiveTo evaluate the cost-effectiveness of a population-based lung cancer screening program from the perspective of a German payer.MethodsWe conducted a cost-effectiveness analysis from the public payer perspective for a high-risk population defined as heavy former and current smokers (≥ 20 cigarettes per day) between 55 and 75 years of age. The underlying model consisted of two Markov models. We differentiated between a population-based annual screening program and standard clinical care. Depending on stage at diagnosis, simulated patients were assigned to one of five treatment paths according to the German clinical guideline for the diagnosis and treatment of lung cancer. Costs, life years saved, and quality adjusted life years (QALYs) were used as outcomes. Values for input parameters were taken from the literature. The model was run for 60 cycles with a cycle length of three months. Deterministic and probabilistic sensitivity analyses were conducted.ResultsIn the base case, annual lung cancer screening led to an increase in incremental costs (€ 1,153 per person) compared to standard clinical care. However, the screening approach was associated with an incremental gain in life years (0.06 per person) and QALYs (0.04 per person). Thus, the incremental cost-effectiveness ratio (ICER) was € 19,302 per life year saved and € 30,291 per QALY. A probabilistic sensitivity analysis with 10,000 draws resulted in average ICERs of € 22,118 per life year and € 34,841 per QALY.ConclusionWe provide evidence that lung cancer screening for a high-risk population may be more effective, but also more costly, than standard clinical care from the perspective of a German payer.
       
  • Definitive Treatment Patterns and Survival in Stage II Non-Small Cell Lung
           Cancer
    • Abstract: Publication date: Available online 24 July 2018Source: Lung CancerAuthor(s): Sherry X. Yan, Muhammad M. Qureshi, Kei Suzuki, Michael Dyer, Minh Tam Truong, Virginia Litle, Kimberley S. MakABSTRACTObjectivesThis study delineated definitive treatment patterns for Stage II non-small cell lung cancer (NSCLC) in the United States and evaluated survival by treatment approach.Materials and MethodsPatients with clinically-staged Stage II NSCLC treated with surgery-based therapy, chemoradiation, conventionally-fractionated radiation (CFR), or stereotactic body radiotherapy (SBRT) were identified using the National Cancer Database (NCDB). Median survival was estimated using Kaplan-Meier analysis. Crude and adjusted hazard ratios (HR) and 95% confidence intervals were computed using Cox regression modeling.ResultsBetween 2004-2012, 19,749 patients met study criteria: 13,382 (67.8%) underwent surgery-based treatment, 4,310 (21.8%) received chemoradiation, 1,606 (8.1%) received CFR, and 451 (2.3%) received SBRT. Surgery and SBRT utilization increased over time while CFR and chemoradiation decreased (all p ≤ 0.002). Patients receiving radiation-based treatments were older, with more comorbidities, and higher T/N stage (all p 
       
  • CAPACITY: A physical activity self-management program for patients
           undergoing surgery for lung cancer, a phase I feasibility study
    • Abstract: Publication date: Available online 23 July 2018Source: Lung CancerAuthor(s): Catherine L. Granger, Louis Irving, Phillip Antippa, Lara Edbrooke, Selina M. Parry, Mei Krishnasamy, Linda Denehy ObjectivesPhysical activity is important in lung cancer, yet the majority of patients do not meet minimum weekly recommended activity levels. The objectives of this study were to determine the: 1) feasibility and 2) exploratory effectiveness of a physical activity self-management program aiming to increase physical activity levels of patients undergoing surgery for lung cancer.Materials and MethodsProspective case series including patients with operable lung cancer. The physical activity self-management program, based on international cancer physical activity guidelines, commenced pre-operative (if recruitment occurred ≥7 days before surgery) or post-operative if not, and continued until 8-weeks after surgery. The program included prescription of an unsupervised home aerobic exercise program, taught in an initial face-to-face consultation and followed-up with weekly telephone consultations. This was supplemented with patient education, behaviour change techniques and provision of an activity monitor. The primary endpoint was program feasibility including consent rate and number of consultations delivered. In addition, self-reported physical activity levels, self-efficacy for physical activity, health-related quality of life (HRQoL) and mood was assessed pre- and 8-weeks post-operative.ResultsThe consent rate was 89%. Thirty-seven patients (54% male, mean age 66 ± 10 years) were included. Only six participants commenced the program before surgery, with most (n = 31) commencing post-operatively. The median [IQR] number of consultations was 4 [[3], [4], [5], [6]] per participant. There was no change in physical activity levels (total estimated mets/week pre-operative median [IQR] 1066 [0-2772], 8 weeks post-operative 924 [346-1752], p = 0.545) or sedentary time (television viewing hours/day pre-operative 4.5 [2.0-9.5], 8-weeks 4.0 [3.0-5.0], p = 0.527) after surgery.ConclusionThe physical activity program was feasible when implemented in the post-operative setting. Participants in this feasibility study demonstrated maintenance in physical activity levels 8-weeks after surgery, compared with published literature reporting decline after surgery. A randomised controlled trial is warranted to further investigate potential effectiveness of this intervention.
       
  • Does presentation at multidisciplinary team meetings improve lung cancer
           survival' Findings from a consecutive cohort study
    • Abstract: Publication date: Available online 23 July 2018Source: Lung CancerAuthor(s): Emily Stone, Nicole Rankin, Stephen Kerr, Kwun Fong, David C Currow, Jane Phillips, Tess Bewes, Lorena Zhang, Tim Shaw BackgroundMultidisciplinary team (MDT) presentation in lung cancer has the potential to improve longterm outcomes, although this varies between studies. This study aims to evaluate outcomes including survival, according to MDT presentation and to explore the utility of data obtained from local clinical sources.Patients and methodsProspective cases of lung cancer recorded in our institution’s cancer registry were analyzed according to MDT presentation for patient and tumour characteristics, adjusted survival and referral to palliative care.Results1197 cases were included, 295 (24.6%) with MDT presentation and 902 (75.4%) without. 60% of patients were male with median (IQR) age at diagnosis of 70 years (62-78). Histopathology distribution (non-small cell lung cancer and small-cell lung cancer) was similar between the two groups. Compared with the non-MDT group, the MDT group had (1) ECOG score recorded more often (71.9% vs. 47.6%), (2) higher proportion of ECOG 0 cases (31.2% vs. 11.9%) and ECOG 1 cases (28.8% vs. 20.3%), (3) higher proportion of early stage disease (stage I - 23.1% vs. 9.7% stage II - 10.2% vs. 4.8%, stage IIIA - 14.6% vs 6.3%) and (4) lower proportion of metastatic disease (stage IV - 39.3% vs. 56.1%). Referral to palliative care was incompletely recorded in both groups (MDT: n = 116/295, 39.3%; non-MDT: n = 430, 47.7%) but did not differ significantly for stage IV cases. Survival analyzed by stage was greater in the MDT group at 1, 2 and 5 years for all stages except stage IIIB at 1 year post-diagnosis. Adjusted survival analysis for the entire cohort showed improved survival at 5 years for the MDT group (HR 0.7 (0.58-0.85), p 
       
  • Elongation Factor-2 Kinase (eEF-2K) Expression Is Associated with Poor
           Patient Survival and Promotes Proliferation, Invasion and Tumor Growth of
           Lung Cancer
    • Abstract: Publication date: Available online 21 July 2018Source: Lung CancerAuthor(s): Ahmet Bircan, Nilgun Gurbuz, Apar Pataer, Ayse Caner, Nermin Kahraman, Emine Bayraktar, Recep Bayraktar, Mumin Alper Erdogan, Nashwa Kabil, Bulent Ozpolat ObjectivesLung cancer is the leading cause of cancer related deaths in worldwide. Despite recent advances in treatment options, patient survival has not improved substantially due to lack of commonly expressed molecular targets and effective targeted therapeutics. Thus, better understanding of the biology of lung cancer and identification of novel therapeutic targets are urgently needed for development of highly effective molecularly targeted therapies.Materials and MethodsViability, proliferation and metastatic ability of lung cancer cells were evaluated using methylthiazoltetrazolium (MTT), colony formation and matrigel invasion assays, respectively. Western blotting, RT-PCR, and gene knockdown by siRNA transfections were carried out to investigate the effects of eEF-2 K on lung cancer cells. Athymic Nu/Nu mice were treated with liposomal eEF-2 K or control siRNAs and tumor growth was evaluated in vivo tumor xenograft models of lung cancer.Results and discussionHere, we report that Eukaryotic Elongation Factor-2 kinase (eEF-2 K), a member of an atypical alpha kinases family, is significantly upregulated in lung cancer cell lines and its expression is associated with shorter overall patient survival in lung cancer. Inhibition eEF-2 K expression by siRNA or a chemical inhibitor significantly suppressed lung cancer cell proliferation, colony formation, survival, migration/invasion and tumorigenesis by inhibiting cyclin D1, Src and Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinase (MAPK/ERK) signaling. In vivo targeting of eEF-2 K by systemically injected nanoliposomal eEF-2 K siRNA resulted in a significant inhibition of tumor xenografts in nude mice. Our results suggest, for the first time, that expression of eEF-2 K is associated with poor patient prognosis and involved in regulation of critical pathways including Src and MAPK/ERK and cyclin D1, promoting tumor growth and progression, and thus may be a novel potential therapeutic target in lung cancer.
       
  • Lung cancer screening – gaining consensus on next steps – proceedings
           of a closed workshop in the UK
    • Abstract: Publication date: Available online 21 July 2018Source: Lung CancerAuthor(s): J. Moffat, S. Hiom, H.S. Kumar, D.R. Baldwin Lung cancer is the most common cause of cancer death in the UK, and survival from the disease is persistently poor. Efforts to improve outcomes for patients have focused on ways of reducing late diagnosis of the disease, and access to optimal treatment. Research on lung cancer screening has so far provided some evidence of an impact on lung cancer mortality, but there is some debate about whether implementation of a national screening programme should await further trial data, principally that from the NELSON trial. The ongoing poor outcomes and the belief amongst some clinicians that there is sufficient evidence has prompted several local projects testing out lung screening in their communities, sometimes referred to as lung health checks or proactive approaches to high-risk individuals. Funding from NHS England has been forthcoming to support this. Acknowledging roll-out of such activities, which effectively constitute local lung screening in the absence of a NSC recommendation, it was timely to bring key national stakeholders together with academic and clinical experts, to agree a way forward. Cancer Research UK therefore convened a closed workshop in March 2018, involving national and international expertise. This paper outlines the proceedings, key discussion points, highlighted research gaps, and areas of consensus and next steps.
       
  • Circulating endothelial cells and microparticles as diagnostic and
           prognostic biomarkers in small-cell lung cancer
    • Abstract: Publication date: Available online 21 July 2018Source: Lung CancerAuthor(s): Fadi Najjar, Moosheer Alammar, Ghassan Al-Massarani, Nissreen Almalla, Abdulmunim Japawe, Adnan IkhtiarABSTRACTObjectivesIt has been proposed that circulating endothelial cells (CECs) and microparticles (MPs) may be useful for the assessment of patients with non-small-cell lung cancer (NSCLC). However, little is known about the potential clinical relevance of these biomarkers in small-cell lung cancer (SCLC). Therefore, we investigated the utility of baseline levels of CECs and MPs in SCLC patients.Materials and methodsAn immunomagnetic separation (IMS) technique was used to isolate and quantify CECs in the peripheral blood, while plasma samples were analyzed using flow cytometry for the measurement of circulating MPs.ResultsWe prospectively collected data from 56 patients and 41 healthy individuals. Forty-three patients presented at initial diagnosis and 13 patients presented at relapse. Baseline levels of CECs and MPs were significantly higher in SCLC patients either at initial diagnosis or at relapse than in healthy subjects (p < 0.0002 and p < 0.007, respectively). However, estimated tumor volume (ETV) was significantly correlated with basal MP values (p < 0.0001) but not with pretreatment CECs (p =  0.57). The amount of baseline CECs and MPs was significantly lower in patients with an objective response (OR, n = 23) than in those with progressive disease (PD, n = 15) after treatment (p =  0.016 and 0.05, respectively). With cut-off values of 110 cells/mL for CECs and 1257 events/µL for MPs according to receiver operating characteristics (ROC) analysis, baseline levels of these biomarkers were not significantly correlated with either progression-free survival (PFS) or overall survival (OS). However, patients with 6-month PFS displayed significantly decreased pretreatment CEC counts (p =  0.042), whereas basal MP values significantly increased in 1-year survivors compared with those in non-survivors (p =  0.05).ConclusionOur results suggest that baseline CECs and MPs may be predictive biomarkers of tumor response and long-term survival in SCLC patients.
       
  • Tumor-specific genetic variants can be detected in circulating cell-free
           DNA of malignant pleural mesothelioma patients
    • Abstract: Publication date: Available online 21 July 2018Source: Lung CancerAuthor(s): Marieke Hylebos, Ken Op de Beeck, Patrick Pauwels, Karen Zwaenepoel, Jan P. van Meerbeeck, Guy Van CampABSTRACTObjectivesPatients diagnosed with malignant pleural mesothelioma (MPM) face a poor prognosis, with an overall survival plateauing at a median of one year. This can be explained by difficulties in early diagnosis, effective treatment and treatment monitoring. Circulating cell-free tumor DNA (ctDNA) is emerging as an interesting biomarker addressing some of these issues. So far, the development of ctDNA in MPM lags behind that in other tumors. In this study, the possibility of tracing tumor-specific genetic variants, identified in MPM tissue, in circulating DNA of the corresponding patients is investigated.Materials and MethodsWhole exome sequencing was performed on paired tumor and germline DNA of ten MPM patients, of which five were treatment naïve. For each patient, a tumor-specific variant was selected and traced in tumor, germline and circulating DNA using droplet digital PCR in two independent runs.ResultsAll but one tumor-specific variants, selected after whole exome sequencing, were validated on primary tumor tissue using droplet digital PCR analysis. Patient-specific, selected variants could be detected in circulating DNA of three MPM patients, either in one or both independent droplet digital PCR runs. Mutated fractions in circulating DNA ranged from 0.28 to 0.9%. Interestingly, all patients whose circulating DNA samples contained tumor-specific variants, were treatment naïve.ConclusionWe demonstrated for the first time the presence of ctDNA within circulating DNA of treatment naïve MPM patients. This finding opens perspectives towards the use of ctDNA as a biomarker for (early and differential) diagnosis, treatment and treatment monitoring of MPM, which all remain challenging.
       
  • EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma
           harboring an NRG1 fusion
    • Abstract: Publication date: Available online 20 July 2018Source: Lung CancerAuthor(s): Hye Sook Kim, Ji-Youn Han, Dong Hoon Shin, Kun Young Lim, Geon Kook Lee, Jin Young Kim, Wolfgang Jacob, M. Ceppi, Martin Weisser, I. James Rearrangements of NRG1 have been identified in invasive mucinous adenocarcinoma of the lung (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma. NRG1 ligand signals through induction of HER2-HER3 heterodimers, thus leading to PI3K–AKT pathway activation. Therefore, targeting HER2, HER3 and the downstream pathway may be a hypothesis-driven strategy for IMA with NRG1 fusion. Herein we reported two patients who benefited from lumretuzumab, a monoclonal anti-HER3 antibody, in combination of erlotinib during a clinical trial (NCT01482377). At least sixteen weeks of progression-free survival were achieved without any unacceptable toxicity.
       
  • Smoking, alcohol, and nutritional status in relation to one-year mortality
           in Danish stage I lung cancer patients
    • Abstract: Publication date: Available online 20 July 2018Source: Lung CancerAuthor(s): Niels Lyhne Christensen, Anders Løkke, Susanne Oksbjerg Dalton, Jane Christensen, Torben Riis Rasmussen IntroductionIn addition to the highest incidence rate of lung cancer among the Nordic countries, Denmark has the highest mortality rate. Moreover, rates of tobacco and alcohol consumption are among the highest in these countries. Method: In a population-based matched case/control study, we aimed to assess the association between one-year all-cause mortality and a number of smoking-related parameters, high-risk alcohol intake, and nutritional status in clinical stage I lung cancer patients. Results: We included 221 patients who died within one year after diagnosis (early death) and 410 matched controls who survived more than one year (survivor). The odds ratio (OR) for early death among never-smokers was 0.3 (CI 95%: 0.1–0.9). There was no significant difference between patients who died early and survivors in proportions of current smokers (49 vs. 45%), number of cumulated pack-years (45 vs. 46), daily tobacco consumption (15 vs. 14 cigarettes/day), patients who quit smoking after diagnosis (25 vs. 40%) and the prevalence of chronic obstructive pulmonary disease (COPD) (43 vs. 38%). Patients that died early received more medications for COPD (p = 0.03) and smoked more after diagnosis, 14 vs. 10 cigarettes per day (p = 0.03). The unadjusted OR for high-risk alcohol intake was 2.2 (CI 95% 1.3–3.7) in the early death group vs. the survivors. However, in a treatment-stratified analysis this was observed only for surgically treated patients (OR, 3.2; CI 95% 1.7–6.1). Low nutritional status was associated with early death, unadjusted (OR 2.3; CI 95% 1.4–3.7), while OR was 1.8 (95% CI 1.0–2.3) adjusted for high-risk alcohol intake and COPD. Treatment selection according to and interventions against these factors before and after lung cancer diagnosis may improve outcomes.
       
  • Applicability of a prognostic CT-based radiomic signature model trained on
           stage I-III non-small cell lung cancer in stage IV non-small cell lung
           cancer
    • Abstract: Publication date: Available online 20 July 2018Source: Lung CancerAuthor(s): Evelyn E.C. de Jong, Wouter van Elmpt, Stefania Rizzo, Anna Colarieti, Gianluca Spitaleri, Ralph T.H. Leijenaar, Arthur Jochems, Lizza E.L. Hendriks, Esther G.C. Troost, Bart Reymen, Anne-Marie C. Dingemans, Philippe Lambin ObjectivesRecently it has been shown that radiomic features of computed tomography (CT) have prognostic information in stage I-III non-small cell lung cancer (NSCLC) patients. We aim to validate this prognostic radiomic signature in stage IV adenocarcinoma patients undergoing chemotherapy.Materials and MethodsTwo datasets of chemo-naive stage IV adenocarcinoma patients were investigated, dataset 1: 285 patients with CTs performed in a single center; dataset 2: 223 patients included in a multicenter clinical trial. The main exclusion criteria were EGFR mutation or unknown mutation status and non-delineated primary tumor. Radiomic features were calculated for the primary tumor. The c-index of cox regression was calculated and compared to the signature performance for overall survival (OS).ResultsIn total CT scans from 195 patients were eligible for analysis. Patients having a Prognostic Index (PI) lower than the signature median (n = 92) had a significantly better OS than patients with a PI higher than the median (n = 103, HR 1.445, 95% CI 1.07-1.95, p = 0.02, c-index 0.576, 95% CI 0.527-0.624).ConclusionThe radiomic signature, derived from daily practice CT scans, has prognostic value for stage IV NSCLC, however the signature performs less than previously described for stage I-III NSCLC stages. In the future, machine learning techniques can potentially lead to a better prognostic imaging based model for stage IV NSCLC.
       
  • KRAS-Mutant Non-Small Cell Lung Cancer: From Biology to Therapy
    • Abstract: Publication date: Available online 19 July 2018Source: Lung CancerAuthor(s): Irene Ferrer, Jon Zugazagoitia, Stephan Herbertz, William John, Luis Paz-Ares, Gerald Schmid-Bindert In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation.
       
  • Antibody Drug Conjugates in Thoracic Malignancies
    • Abstract: Publication date: Available online 19 July 2018Source: Lung CancerAuthor(s): Jose M. Pacheco, D. Ross Camidge Antibody drug conjugates (ADCs) have the potential to alter the efficacy: toxicity ratio of cytotoxic therapy utilizing surface markers on cancer cells as antibody targets to preferentially deliver toxic payloads to tumor cells while limiting systemic toxicity. Multiple ADCs, differing in their antibody targets, cytotoxic payloads and linker molecules are currently being evaluated in non-small-cell lung cancer, small-cell lung cancer and malignant pleural mesothelioma. Here we review the available data in thoracic malignancies and the potential issues influencing the efficacy and toxicity of these approaches.
       
  • Synchronous multiple non-small cell lung cancers in an allograftlung
           recipient
    • Abstract: Publication date: Available online 19 July 2018Source: Lung CancerAuthor(s): Jean-Louis Pujol, Sandy Jean-Baptiste, Sébastien Bommart, Benoît Roch We described a case report of synchronous non-small cell lungcancers arising in lung transplants after allograft.Immunosuppressive therapy of the recipient induced an accelerated growth rate of primarytumour and metastases as was been observed in orthotopic liverallograft for hepatocellular carcinoma.
       
  • Prediagnosis weight loss, a stronger factor than BMI, to predict survival
           in patients with lung cancer
    • Abstract: Publication date: Available online 5 July 2018Source: Lung CancerAuthor(s): Hugues Morel, Bruno Raynard, Michel d’Arlhac, Pierre-Alexandre Hauss, Emmanuelle Lecuyer, Gérard Oliviero, Clothilde Marty, Jean-Pierre Gury, Bernard Asselain, Michel Grivaux, Didier Debieuvre
       
  • Relationship between the number of new nodules and lung cancer probability
           in incidence screening rounds of CT lung cancer screening: The NELSON
           study
    • Abstract: Publication date: Available online 14 May 2018Source: Lung CancerAuthor(s): Joan E. Walter, Marjolein A. Heuvelmans, Geertruida H. de Bock, Uraujh Yousaf-Khan, Harry J.M. Groen, Carlijn M. van der Aalst, Kristiaan Nackaerts, Peter M.A. van Ooijen, Harry J. de Koning, Rozemarijn Vliegenthart, Matthijs Oudkerk BackgroundNew nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participant’s number of new nodules and lung cancer probability is unknown.MethodsParticipants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participant’s new nodule count and the largest new nodule size was assessed using Spearman's rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed.ResultsIn total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants>1 new nodule was detected (range 1-12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% [56/551], 95%CI 8–13%) or>1 new nodule (6% [9/154], 95%CI 3–11%, P = 0.116). An increased number of new nodules positively correlated with a participant’s largest nodule size (P 
       
  • The novel microRNA smR-164 regulates cell proliferation and apoptosis in
           human lung cancer by targeting XIAP
    • Abstract: Publication date: Available online 13 April 2018Source: Lung CancerAuthor(s): Jung Ki Yoo, Ji Min Lee, Seung Hee Kang, Seong Ho Jeon, Chang Min Kim, Seung-Hun Oh, Chang-Hyun Kim, Nam Keun Kim, Jin Kyeoung Kim ObjectivesMicroRNAs have critical roles in cancer development by regulating the expression of oncogenes or tumor suppressor genes. We identified and characterized a novel miRNA, smR-164, in human lung cancer cells. The aim of this study was to investigate its novel function in human lung cancer by targeting XIAPMaterial and methodsNovel miRNA cloning, Real-time qRT-PCR, western blotting, dual luciferase assay, miRNA transfection, proliferation and apoptosis assay were carried on human lung cancer cell line A549. Fifteen paired NSCLC tissues and noncancerous lung tissues were collected. In vivo xenograft assay was performed.ResultsExpression of smR-164 was downregulated in human lung cancer cell lines and tissues compared with normal cells and tissues. We identified a putative target gene, XIAP, whose expression was regulated by smR-164 overexpression. XIAP is an inhibitor of apoptosis that represses the activation of caspase 3 and 9. XIAP mRNA and protein levels were directly suppressed by smR-164. XIAP has an important role in carcinogenesis, and previous studies suggest that it may regulate cell survival and proliferation by its anti-apoptotic ability.ConclusionTaken together, smR-164 inhibited cell proliferation and induced apoptosis in vitro and in vivo by targeting XIAP. These data can be applied to identify novel therapeutic targets for lung cancer therapy.
       
  • Tumor autoantibodies (TAAs) panel can improve the accuracy of early
           diagnosis in lung cancer presenting with ground-glass nodules (GGNs) in
           Chinese population
    • Abstract: Publication date: Available online 9 February 2018Source: Lung CancerAuthor(s): Yayi He, Shengxiang Ren, Kenichi Suda, Christopher Rivard, Yan Wang, Xuefei Li, Caicun Zhou, Fred R. Hirsch BackgroundAutoantibody is an attractive diagnostic approach for early detection of malignant tumors. We performed this study to validate the performance of a panel of 7 tumor autoantibodies (TAAs) (p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGE A1, CAGE) to aid early diagnosis of lung adenocarcinoma with ground-glass nodules (GGNs) in Chinese population and to find an effective simple blood test which can be used in further assessing the risk of lung cancer being present GGNs.MethodsA prospective audit was conducted on 592 individuals known to have lung GGNs. We detected TAAs quantitation by ELISA method.Results198 were positive detected by autoantibody panel test (186 pulmonary malignant or borderline lung diseases, 12 lung benign GGNs). The sensitivity and specificity of autoantibody assay were 39.6% and 90.2% respectively. In lung invasive adenocarcinoma, the sensitivity of autoantibody assay was 49.4%. When the TAAs were combined with miRNAs panel in patients with GGNs, the sensitive was increased to 50.0%. In GGNs>8 mm patients, the sensitive of the TAAs combined with miRNAs panel was more than 60%.ConclusionThe greatest impact of using the new TAAs was the highly significant improvement in the sensitivity and specificity of the test in the clinical setting. Our study suggested that the TAAs can be combined with CT imaging to aid diagnosis of lung cancer with GGNs.
       
 
 
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