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Tissue Acquisition in Patients with Suspected Lung Cancer: Techniques Available to the Pulmonologist

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Interventions in Pulmonary Medicine

Abstract

The method of diagnosis and staging of lung cancer for the most part depends on the type of lung cancer, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), the size and location of the primary tumor, the stage, and the overall clinical status of the patient. Although it is reassuring that the accuracy of differentiating between SCLC and NSCLC generated by various diagnostic techniques is excellent (Rivera et al. Chest 143(5 Suppl):e142S, 2013), treatment of NSCLC now relies on accurate histopathologic diagnosis and molecular characterization of the tumor. In recent years, we have witnessed a revolution in our understanding of the molecular genotype of lung cancer, and certain molecular determinants not only guide treatment decision-making but also have a prognostic and predictive function. Clinicians who perform diagnostic procedures in lung cancer need to be familiar with the array of options for tissue acquisition as well as the importance of judicious handling of specimens in order to derive the most information from each procedure.

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References

  1. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e142S.

    Article  PubMed  Google Scholar 

  2. Salvaggi G, Scagliotti GV. Histology subtype in NSCLC. Does it matter? Oncology. 2009;23:1133.

    Google Scholar 

  3. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543.

    Article  CAS  PubMed  Google Scholar 

  4. Ciuleanu T, Brodowicz T, Zielinski JHK, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small cell lung cancer: a randomized, double –blind, phase 3 study. Lancet. 2009;374:1432.

    Article  CAS  PubMed  Google Scholar 

  5. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical and response to gefitinib therapy. Science. 2004;304:1497.

    Article  CAS  PubMed  Google Scholar 

  6. Lynch TB, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129.

    Article  CAS  PubMed  Google Scholar 

  7. Maemondo M, Inuoe A, Kobayshi K, et al. Gefitinib or chemotherapy for non-small cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380.

    Article  CAS  PubMed  Google Scholar 

  8. Zhou C, YL W, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment of patients with advanced EGFR mutation positive NSCLC. A multicenter, open label, randomized phase 3 study. Lancet Oncol. 2011;12:735.

    Article  CAS  PubMed  Google Scholar 

  9. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology Provisional Clinical Opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small cell lung cancer considering first –line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;4:1.

    Google Scholar 

  10. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. N Engl J Med. 2010;363:1693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bergethon K, Shaw AT, Ou AH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Villaruz LC, Burns TF, Ramfidis VS, et al. Personalizing therapy in advanced non-small cell lung cancer. Semin Respir Crit Care Med. 2013;34:822.

    Article  PubMed  PubMed Central  Google Scholar 

  13. FDA approves Keytruda for advanced non-small cell lung cancer. [news release]. Silver Spring, MD: FDA; 2015.

    Google Scholar 

  14. Travis WB, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Adenocarcinoma. J Thorac Oncol. 2011;6:244.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Schreiber G, McCrory DC. Performance characteristics of different modalities for diagnosis of suspected lung cancer: summary of published evidence. Chest. 2003;123:115.

    Article  Google Scholar 

  16. Thunnissen E, Kerr KM, Herth FJF, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer. 2012;76(1):1–18.

    Article  PubMed  Google Scholar 

  17. Coghlin CL, Smith LJ, Bakar S, et al. Quantitative analysis of tumor in bronchial biopsy specimens. J Thorac Oncol. 2010;5:448.

    Article  PubMed  Google Scholar 

  18. Kacar N, Tuksavul F, Edipoglu O, et al. Effectiveness of trans- bronchial needle aspiration in the diagnosis of exophytic endobronchial lesions and submucosal/peribronchial diseases of the lung. Lung Cancer. 2005;50:221.

    Article  PubMed  Google Scholar 

  19. Harrow EM, Bi-Saleh W, Blum J, et al. The utility of transbronchial needle aspiration in the staging of bronchogenic carcinoma. Am J Respir Crit Care Med. 2000;161:601.

    Article  CAS  PubMed  Google Scholar 

  20. Toloza EM, Harpole L, Detterbeck F, et al. Invasive staging of non-small cell lung cancer: a review of the current evidence. Chest. 2003;123:157.

    Article  Google Scholar 

  21. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2013;143(5 Suppl):e211S.

    Article  PubMed  Google Scholar 

  22. Yasufuku K, Fujisawa T. Staging and diagnosis of non-small cell lung cancer: invasive modalities. Respirology. 2007;12:173.

    Article  PubMed  Google Scholar 

  23. Abram D, Garcia RB, Richman PS. Impact of rapid on-site cytologic evaluation during transbronchial needle aspiration. Chest. 2005;128:869.

    Article  Google Scholar 

  24. Herth F, Becker HD, Ernst A. Conventional vs. endobronchial ultrasound–guided transbronchial needle aspiration: a randomized trial. Chest. 2004;125:322.

    Article  PubMed  Google Scholar 

  25. Herth FJ, Eberhardt R. Actual role of endobronchial ultrasound (EBUS). Eur Radiol. 2007;17:1806.

    Article  PubMed  Google Scholar 

  26. Herth FJ, Eberhardt R, Vilmann P, et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61:795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Krasnik M, Vilmann P, Larsen SS, et al. Preliminary experience with a new method of endoscopic transbronchial real time ultrasound guided biopsy for diagnosis of mediastinal and hilar lesions. Thorax. 2003;58:1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Annema JT, Rabe KF. State of the art lecture: EUS and EBUS in pulmonary medicine. Endoscopy. 2006;38(suppl 1):S118–22.

    Article  PubMed  Google Scholar 

  29. Yasafuko K, Chiyo M, Koh E, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer. 2005;50:347.

    Article  Google Scholar 

  30. Kennedy MP, Jimenez CA, Morice RC, et al. Factors influencing the diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration. J Bronchology Interv Pulmonol. 2010;17:202.

    Article  PubMed  Google Scholar 

  31. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound- guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45:1389.

    Article  PubMed  Google Scholar 

  32. Herth FJ, Ernst A, Eberhardt R, et al. Endobronchial ultrasound–guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum. Eur Respir J. 2006;28:910.

    Article  CAS  PubMed  Google Scholar 

  33. Herth FJF, Eberhardt R, Krasnik M, et al. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest. 2008;133:887.

    Article  PubMed  Google Scholar 

  34. Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy versus endosonography for mediastinal staging of lung cancer. A randomized trial. JAMA. 2010;304:2245.

    Article  CAS  PubMed  Google Scholar 

  35. Steinfort DP, Conron M, Tsui A, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for the evaluation of suspected lymphoma. J Thorac Oncol. 2010;5:804.

    Article  PubMed  Google Scholar 

  36. Kennedy MP, Jimenez CA, Bruzzi JF, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lymphoma. Thorax. 2008;63:360.

    Article  CAS  PubMed  Google Scholar 

  37. Tournoy KG, Govaerts E, Malfait T, et al. Endobronchial ultrasound-guided transbronchial needle biopsy for M1 staging of extrathoracic malignancies. Ann Oncol. 2011;22:127.

    Article  CAS  PubMed  Google Scholar 

  38. Garwood S, Judson MA, Silvestri G, et al. Endobronchial ultrasound for the diagnosis of pulmonary sarcoid. Chest. 2008;133:1529.

    Article  PubMed  Google Scholar 

  39. Fritscher-Ravens A, Soehendra N, Schirrow L, et al. Role of transesophageal endosonography–guided fine-needle aspiration in the diagnosis of lung cancer. Chest. 2000;117:339.

    Article  CAS  PubMed  Google Scholar 

  40. Eloubeidi MA, Cerfolio RJ, Chen VK, et al. Endoscopic ultrasound-guided fine needle aspiration of mediastinal lymph node in patients with suspected lung cancer after positron emission tomography and computed tomography scans. Ann Thorac Surg. 2005;79:263.

    Article  PubMed  Google Scholar 

  41. Bodtger U, Vilmann P, Clementsen P, et al. Clinical impact of endoscopic ultrasound-fine needle aspiration of left adrenal masses in established or suspected lung cancer. J Thorac Oncol. 2009;4:1485.

    Article  PubMed  Google Scholar 

  42. Rintoul RC, Skwarski KM, Murchison JT, et al. Endobronchial and endoscopic ultrasound-guided real-time fine-needle aspiration for mediastinal staging. Eur Respir J. 2005;25:416.

    Article  CAS  PubMed  Google Scholar 

  43. Vilmann P, Krasnik M, Larsen SS, et al. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy. 2005;37:833.

    Article  CAS  PubMed  Google Scholar 

  44. Herth FJF, Krasnik M, Kahn N, et al. Combined endoscopic- endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer. Chest. 2010;138:790.

    Article  PubMed  Google Scholar 

  45. Gildea TR, Mazzone PJ, Karnak D, et al. Electromagnetic navigation diagnostic bronchoscopy. A prospective study. Am J Respir Crit Care Med. 2006;174:982.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Eberhardt R, Anantham D, Herth F, et al. Electromagnetic navigation diagnostic bronchoscopy in peripheral lung lesions. Chest. 2007;131:1800.

    Article  PubMed  Google Scholar 

  47. Lamprecht B, Porsch P, Pirich C, et al. Electromagnetic navigation bronchoscopy in combination with PET-CT and rapid on-site cytopathologic examination for diagnosis of peripheral lung lesions. Lung. 2009;187:55.

    Article  PubMed  Google Scholar 

  48. Eberhardt R, Anantham D, Ernst A, et al. Multimodality bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J Respir Crit Care Med. 2007;176:36.

    Article  PubMed  Google Scholar 

  49. Yarmus LB, Arias S, Feller-Kopman D, et al. Electromagnetic navigation transthoracic needle aspiration for the diagnosis of pulmonary nodules: a safety and feasibility pilot study. J Thorac Dis. 2016;81:186.

    Google Scholar 

  50. Tremblay A. Real-time electromagnetic navigation bronchoscopy for peripheral lesions: what about the negative predictive value? Chest. 2007;131:328.

    Article  PubMed  Google Scholar 

  51. Anantham D, Feller-Kopman D, Shanmugham LN, et al. Electromagnetic navigation bronchoscopy-guided fiducial placement for robotic stereotactic radiosurgery of lung tumors: a feasibility study. Chest. 2007;132:930.

    Article  PubMed  Google Scholar 

  52. Harley DP, Krimsky WS, Sarkar S, et al. Fiducial marker placement using endobronchial ultrasound and navigational bronchoscopy for stereotactic radiosurgery: an alternative strategy. Ann Thorac Surg. 2010;89:368.

    Article  PubMed  Google Scholar 

  53. Steinfort DP, Khor YH, Manser RL, et al. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta analysis. Eur Respir J. 2011;37:902.

    Article  CAS  PubMed  Google Scholar 

  54. Chen A, Chenna P, Loiselle A, et al. Radial probe endobronchial ultrasound for peripheral pulmonary lesions. A 5-year institutional experience. Ann Am Thorac Soc. 2014;1:578–82.

    Article  Google Scholar 

  55. Memoli Wang JS, Nietert PJ, Silvestri G. Meta-analysis of guided bronchoscopy for the evaluation of the pulmonary nodule. Chest. 2011;140:1550.

    Article  Google Scholar 

  56. Casal RE, Staerkel GA, Ost D, et al. Randomized clinical trial of endobronchial ultrasound needle biopsy with and without aspiration. Chest. 2012;142:568.

    Article  PubMed  Google Scholar 

  57. Diacon AH, Koegelenberg CF, Schubert P, et al. Rapid on-site evaluation of transbronchial aspirates: randomised comparison of two methods. Eur Respir J. 2010;35:1216.

    Article  CAS  PubMed  Google Scholar 

  58. Lee HS, Lee GK, Lee HS, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of non-small cell lung cancer: how many aspirations per target lymph node station? Chest. 2008;134:368.

    Article  PubMed  Google Scholar 

  59. Navani N, Brown JM, Nankivell M, et al. Suitability of endobronchial ultrasound-guided transbronchial needle aspiration specimens for subtyping and genotyping of non-small cell lung cancer: a multicenter study of 774 patients. Am J Respir Crit Care Med. 2012;185:1316.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Billah S, Stewart J, Staerkel G, Chen S, Gong Y, Guo M. EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens. Cancer Cytopathol. 2011;119:111.

    Article  CAS  PubMed  Google Scholar 

  61. Tanner NT, Watson P, Boylan A, et al. Utilizing endobronchial ultrasound with fine-needle aspiration to obtain tissue for molecular analysis: a single-center experience. J Bronchology Interv Pulmonol. 2011;18:317.

    Article  PubMed  Google Scholar 

  62. Nakajima T, Yasufuku K, Nakagawara A, Kimura H, Yoshino I. Multigene mutation analysis of metastatic lymph nodes in non-small cell lung cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2011;140:1319–2.

    Article  PubMed  Google Scholar 

  63. Yarmus LB, Akulian J, Lechtzin N, et al. Comparison of 21-gauge and 22-gauge aspiration needle in endobronchial ultrasound-guided transbronchial needle aspiration: results of the American College of Chest Physicians Quality Improvement Registry, Education, and Evaluation Registry. Chest. 2013;143:1036.

    Article  PubMed  Google Scholar 

  64. Nakajima T, Yasufuku K, Takahashi R, et al. Comparison of 21-gauge and 22-gauge aspiration needle during endobronchial ultrasound-guided transbronchial needle aspiration. Respirology. 2011;16:90.

    Article  PubMed  Google Scholar 

  65. Roh MH. The utilization of cytologic fine needle aspirates for molecular diagnostic testing. J Pathol Transl Med. 2015;49:300.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR. PLoS One. 2011;6:e17791.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Mohamed S, Yasufuku K, Nakajima T, et al. Analysis of cell cycle-related proteins in mediastinal lymph nodes of patients with N2-NSCLC obtained by EBUS-TBNA: relevance to chemotherapy response. Thorax. 2008;63:64.

    Article  Google Scholar 

  69. Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of chemosensitivity-related aberrant methylation of non-small cell lung cancer by EBUS-TBNA. J Bronchology Intervent Pulmonol. 2009;16:10.

    Article  Google Scholar 

  70. Schuurbiers OCJ, Looijen-Salamon MG, Ligtenberg MJL, et al. A brief retrospective report on the feasibility of epidermal growth factor receptor and KRAS mutation analysis in transesophageal ultrasound- and endobronchial ultrasound-guided fine needle cytological aspirates. J Thorac Oncol. 2010;5:1664.

    Article  PubMed  Google Scholar 

  71. Smouse JH, Cibas ES, Jänne PA, et al. EGFR mutations are detected comparably in cytologic and surgical pathology specimens of non-small cell lung cancer. Cancer Cytopathol. 2009;117:67.

    Article  Google Scholar 

  72. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2007;132:597.

    Article  CAS  PubMed  Google Scholar 

  74. Nakajima T, Yasufuku K. How I do it – optimal methodology for multidirectional analysis of endobronchial ultrasound-guided transbronchial needle aspiration samples. J Thorac Oncol. 2011;6:203.

    Article  PubMed  Google Scholar 

  75. Jeyabalan A, Bhatt N, Plummeridge MJ, et al. Adequacy of endobronchial ultrasound-guided transbronchial needle aspiration samples processed as histopathological samples for genetic mutation analysis. Mol Clin Oncol. 2016;4:119.

    Article  PubMed  Google Scholar 

  76. Sakairi Y, Nakajima T, Yasufuku K, et al. EML4- ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Clin Cancer Res. 2010;16:4938.

    Article  CAS  PubMed  Google Scholar 

  77. Tamb Y, Sakakibara R, Moto N, et al. Feasibility of EBUS-TBNA specimens for PDL-1 expression test in lung cancer. J Clin Oncol. 2016;34(Suppl, abstract e23112)

    Google Scholar 

  78. Trisolini R, Cancellieri A, Tinelli C, et al. Rapid on-site evaluation of transbronchial aspirates in the diagnosis of hilar and mediastinal adenopathy: a randomized trial. Chest. 2011;139:395.

    Article  PubMed  Google Scholar 

  79. Yarmus L, Van der Kloot T, Lechtzin N, et al. A randomized prospective trial of the utility of rapid on-site evaluation of transbronchial needle aspirate specimens. J Bronchol Interv Pulmonol. 2011;18:121.

    Article  Google Scholar 

  80. Erickson RA, Sayage-Rabie L, Beissner RS. Factors predicting the number of EUS-guided fine-needle passes for diagnosis of pancreatic malignancies. Gastrointest Endosc. 2005;51:184.

    Article  Google Scholar 

  81. Gaspirini S. It is time for this ROSE to flower. Respiration. 2005;72:129.

    Article  Google Scholar 

  82. Davenport RD. Rapid on-site evaluation of transbronchial aspirates. Chest. 1990;98:59.

    Article  CAS  PubMed  Google Scholar 

  83. Feller-Kopman D, Yung RC, Burroughs F, Li QK. Cytology of endobronchial ultrasound-guided transbronchial needle aspiration: a retrospective study with histology correlation. Cancer. 2009;117:482.

    PubMed  Google Scholar 

  84. Yung RC, Otell S, Illei P, et al. Improvement of cellularity on cell block preparations using the so-called tissue coagulum clot method during endobronchial ultrasound-guided transbronchial fine-needle aspiration. Cancer Cytopathol. 2012;120:185–95.

    Article  PubMed  Google Scholar 

  85. Yasufuku K, Chiyo M, Sekine Y, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest. 2004;126:122.

    Article  PubMed  Google Scholar 

  86. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. HA Y, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240.

    Article  Google Scholar 

  88. Treece AL, Montgomery ND, Patel NM, et al. FNA smears as a potential source of DNA for targeted next-generation sequencing of lung adenocarcinomas. Cancer Cytopathol. 2016;124:406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to M. Patricia Rivera MD .

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Akulian, J.A., Patricia Rivera, M. (2018). Tissue Acquisition in Patients with Suspected Lung Cancer: Techniques Available to the Pulmonologist. In: Díaz-Jimenez, J., Rodriguez, A. (eds) Interventions in Pulmonary Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-58036-4_18

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