Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma

Expert Review of Anticancer Therapy

Volumn 12, Issue 9, 2012, Pages 1149-1159

  Markovic, Ana ^a   Chung, Christine H ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

epidermal growth factor receptor; head and neck squamous cell carcinoma; HER tyrosine kinase receptor family; therapeutic monoclonal antibody; tyrosine kinase inhibitor

Indexed keywords

AFATINIB; ANTHRACYCLINE; BIOLOGICAL MARKER; CETUXIMAB; CISPLATIN; DACOMITINIB; EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY; ERLOTINIB; GEFITINIB; LAPATINIB; METHOTREXATE; MONOCLONAL ANTIBODY; PANITUMUMAB; PLACEBO; PLATINUM; PROTEIN TYROSINE KINASE INHIBITOR; TAXANE DERIVATIVE; TRASTUZUMAB; ZALUTUMUMAB;

ACNE; ANEMIA; BREAST METASTASIS; CANCER RESISTANCE; COLORECTAL CANCER; DERMATITIS; DIARRHEA; DRUG DOSE COMPARISON; DRUG ERUPTION; DRUG HALF LIFE; DRUG MECHANISM; FATIGUE; HAND FOOT SYNDROME; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; HYPOMAGNESEMIA; INFUSION RELATED REACTION; METASTASIS; MOLECULARLY TARGETED THERAPY; NASOPHARYNX CARCINOMA; NEUTROPENIA; PNEUMONIA; PREDICTION; RECURRENT CANCER; REVIEW; SKIN MANIFESTATION; SKIN TOXICITY; WART VIRUS;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CARCINOMA, SQUAMOUS CELL; CLINICAL TRIALS AS TOPIC; DISEASE MANAGEMENT; DRUGS, INVESTIGATIONAL; HEAD AND NECK NEOPLASMS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASM METASTASIS; NEOPLASM RECURRENCE, LOCAL; PAPILLOMAVIRUS INFECTIONS; PROTEIN-TYROSINE KINASES; RECEPTOR, EPIDERMAL GROWTH FACTOR; SURVIVAL ANALYSIS; THERAPEUTIC EQUIVALENCY; TREATMENT OUTCOME;

EID: 84867950688     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/era.12.91     Document Type: Review

References (84)

1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA. Cancer J. Clin. 61(4), 212-236 (2011).
2. Hashibe M, Brennan P, Benhamou S et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J. Natl Cancer Inst. 99(10), 777-789 (2007). (Pubitemid 47073524)
3. Hashibe M, Brennan P, Chuang SC et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol. Biomarkers Prev. 18(2), 541-550 (2009).
4. D'Souza G, Kreimer AR, Viscidi R et al. Case-control study of human papillomavirus and oropharyngeal cancer. N. Engl. J. Med. 356(19), 1944-1956 (2007). (Pubitemid 46740304)
5. Bernier J, Domenge C, Ozsahin M et al. European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N. Engl. J. Med. 350(19), 1945-1952 (2004). (Pubitemid 38580197)
6. Cooper JS, Pajak TF, Forastiere AA et al. Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 350(19), 1937-1944 (2004).
7. Forastiere AA, Goepfert H, Maor M et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N. Engl. J. Med. 349(22), 2091-2098 (2003). (Pubitemid 37464533)
8. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359(11), 1116-1127 (2008).
9. Ang KK, Berkey BA, Tu X et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 62(24), 7350-7356 (2002). (Pubitemid 36025259)
10. Chung CH, Zhang Q, Hammond EM et al. Integrating epidermal growth factor receptor assay with clinical parameters improves risk classification for relapse and survival in head-and-neck squamous cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 81(2), 331-338 (2011).
11. Ang KK, Harris J, Wheeler R et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl.J. Med. 363(1), 24-35 (2010).
12. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354(6), 567-578 (2006). (Pubitemid 43209104)
13. Kumar B, Cordell KG, Lee JS et al. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J. Clin. Oncol. 26(19), 3128-3137 (2008).
14. Bianco R, Gelardi T, Damiano V, Ciardiello F, Tortora G. Rational bases for the development of EGFR inhibitors for cancer treatment. Int. J. Biochem. Cell Biol. 39(7-8), 1416-1431 (2007). (Pubitemid 47031050)
15. Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp. Cell Res. 284(1), 2-13 (2003). (Pubitemid 36331964)
16. Arteaga CL, Baselga J. Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them? Cancer Cell 5(6), 525-531 (2004). (Pubitemid 38748914)
17. Galer CE, Corey CL, Wang Z et al. Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma. Head Neck 33(2), 189-198 (2011).
18. Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827), 1039-1043 (2007). (Pubitemid 46799492)
19. Rubin Grandis J, Melhem MF, Gooding WE et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J. Natl Cancer Inst. 90(11), 824-832 (1998). (Pubitemid 28280548)
20. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 53(15), 3579-3584 (1993). (Pubitemid 23229640)
21. Chung CH, Ely K, McGavran L et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J. Clin. Oncol. 24(25), 4170-4176 (2006). (Pubitemid 46622295)
22. Cohen EE, Lingen MW, Martin LE et al. Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR. Clin. Cancer Res. 11(22), 8105-8108 (2005). (Pubitemid 41698754)
23. Lee JW, Soung YH, Kim SY et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin. Cancer Res. 11(8), 2879-2882 (2005).
24. Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin. Exp. Immunol. 158(1), 1-9 (2009).
25. Britten CD. Targeting ErbB receptor signaling: a pan-ErbB approach to cancer. Mol. Cancer Ther. 3(10), 1335-1342 (2004). (Pubitemid 39440177)
26. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125(6), 1137-1149 (2006). (Pubitemid 43866200)
27. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7(4), 301-311 (2005). (Pubitemid 40544648)
28. López-Albaitero A, Ferris RL. Immune activation by epidermal growth factor receptor specific monoclonal antibody therapy for head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 133(12), 1277-1281 (2007). (Pubitemid 350294259)
29. Kurai J, Chikumi H, Hashimoto K et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin. Cancer Res. 13(5), 1552-1561 (2007). (Pubitemid 46450447)
30. Vermorken JB, Trigo J, Hitt R et al. Open-label, uncontrolled, multicenter Phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinumbased therapy. J. Clin. Oncol. 25(16), 2171-2177 (2007). (Pubitemid 46954639)
31. Rowan K. Should cetuximab replace cisplatin in head and neck cancer? J. Natl Cancer Inst. 102(2), 74-6, 78 (2010).
32. Tejani MA, Cohen RB, Mehra R. The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. Biologics 4, 173-185 (2010).
33. Martin NV, Pacifico V, Lai SE et al. Management of rash to erlotinib (E) and cetuximab (C): results from the SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinases) clinic algorithm. J. Clin. Oncol. 25(18 Suppl.), Abstract 19556 (2007).
34. Stewart JS, Cohen EE, Licitra L et al. Phase II study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J. Clin. Oncol. 27(11), 1864-1871 (2009).
35. Licitra L, Mesia R, Rivera F et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann. Oncol. 22(5), 1078-1087 (2011).
36. Cohen EE, Kane MA, List MA et al. Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin. Cancer Res. 11(23), 8418-8424 (2005). (Pubitemid 41746956)
37. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J. Clin. Oncol. 23(34), 8646-8654 (2005). (Pubitemid 46211507)
38. Sok JC, Coppelli FM, Thomas SM et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin. Cancer Res. 12(17), 5064-5073 (2006). (Pubitemid 44453332)
39. Bigner SH, Humphrey PA, Wong AJ et al. Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res. 50(24), 8017-8022 (1990).
40. Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc. Natl Acad. Sci. USA 87(21), 8602-8606 (1990).
41. Chen LF, Cohen EE, Grandis Jr. New strategies in head and neck cancer: understanding resistance to epidermal growth factor receptor inhibitors. Clin. Cancer Res. 16(9), 2489-2495 (2010).
42. Jutten B, Dubois L, Li Y et al. Binding of cetuximab to the EGFRvIII deletion mutant and its biological consequences in malignant glioma cells. Radiother. Oncol. 92(3), 393-398 (2009).
43. Wheeler SE, Suzuki S, Thomas SM et al. Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation. Oncogene 29(37), 5135-5145 (2010).
44. Wheeler DL, Huang S, Kruser TJ et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27(28), 3944-3956 (2008). (Pubitemid 351913636)
45. Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biol. Ther. 11(9), 777-792 (2011).
46. Yonesaka K, Zejnullahu K, Okamoto I et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3(99), 99ra86 (2011).
47. Dempke WC, Heinemann V. Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. Eur. J. Cancer 45(7), 1117-1128 (2009).
48. Almendro V, García-Recio S, Gascón P. Tyrosine kinase receptor transactivation associated to G protein-coupled receptors. Curr. Drug Targets 11(9), 1169-1180 (2010).
49. Frederick BA, Helfrich BA, Coldren CD et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol. Cancer Ther. 6(6), 1683-1691 (2007). (Pubitemid 46954044)
50. Holz C, Niehr F, Boyko M et al. Epithelialmesenchymal- transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells. Radiother. Oncol. 101(1), 158-164 (2011).
51. Basu D, Nguyen TT, Montone KT et al. Evidence for mesenchymal-like subpopulations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity. Oncogene 29(29), 4170-4182 (2010).
52. Skvortsova I, Skvortsov S, Raju U et al. Epithelial-to-mesenchymal transition and c-myc expression are the determinants of cetuximab-induced enhancement of squamous cell carcinoma radioresponse. Radiother. Oncol. 96(1), 108-115 (2010).
53. Saadeh CE, Lee HS. Panitumumab: a fully human monoclonal antibody with activity in metastatic colorectal cancer. Ann. Pharmacother. 41(4), 606-613 (2007). (Pubitemid 46625483)
54. Rischin D, Spigel DR, Adkins D et al. Panitumumab (pmab) regimen in second-line monotherapy (PRISM) in patients (pts) with recurrent (R) or metastatic (M) squamous cell carcinoma of the head and neck (SCCHN): interim safety analysis. Ann. Oncol. 21(Suppl. 8), Abstract 1036P (2010).
55. Vermorken JB, Stohlmacher J, Davidenko I et al. Primary efficacy and safety results of SPECTRUM, a Phase 3 trial in patients (pts) with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) receiving chemotherapy with or without panitumumab (pmab). Ann. Oncol. 21(Suppl. 8), Abstract LBA26 (2010).
56. Patel D, Guo X, Ng S et al. IgG isotype, glycosylation, and EGFR expression determine the induction of antibodydependent cellular cytotoxicity in vitro by cetuximab. Hum. Antibodies 19(4), 89-99 (2010).
57. Schneider-Merck T, Trepel M. Lapatinib. Recent Results Cancer Res. 184, 45-59 (2010).
58. Desjarlais JR, Lazar GA, Zhukovsky EA, Chu SY. Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. Drug Discov. Today 12(21-22), 898-910 (2007). (Pubitemid 350052671)
59. Machiels JP, Subramanian S, Ruzsa A et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised Phase 3 trial. Lancet Oncol. 12(4), 333-343 (2011).
60. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8(4), 303-306 (2003). (Pubitemid 36929716)
61. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter Phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J. Clin. Oncol. 22(1), 77-85 (2004). (Pubitemid 41095117)
62. Cohen EE, Rosen F, Stadler WM et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J. Clin. Oncol. 21(10), 1980-1987 (2003). (Pubitemid 46606387)
63. Kondo N, Tsukuda M, Ishiguro Y et al. Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma. Oncol. Rep. 23(4), 957-963 (2010).
64. Harrington KJ, Berrier A, Robinson M et al. Phase II study of oral lapatinib, a dual-tyrosine kinase inhibitor, combined with chemoradiotherapy (CRT) in patients (pts) with locally advanced, unresected squamous cell carcinoma of the head and neck (SCCHN). J. Clin. Oncol. 28(15S), Abstract 5505 (2010).
65. Del Campo JM, Hitt R, Sebastian P et al. Effects of lapatinib monotherapy: results of a randomised Phase II study in therapynaive patients with locally advanced squamous cell carcinoma of the head and neck. Br. J. Cancer 105(5), 618-627 (2011).
66. de Souza JA, Davis DW, Zhang Y et al. A Phase II study of lapatinib in recurrent/ metastatic squamous cell carcinoma of the head and neck. Clin. Cancer Res. 18(8), 2336-2343 (2012).
67. Harrington KJ, Berrier A, Robinson M et al. Phase II study of oral lapatinib, a dualtyrosine kinase inhibitor, combined with chemoradiotherapy (CRT) in patients (pts) with locally advanced, unresected squamous cell carcinoma of the head and neck (SCCHN). Presented at: 46th Annual Meeting of the American Society of Clinical Oncology. Chicago, IL, USA, 4-8 June 2010.
68. Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34), 4702-4711 (2008).
69. Yamamoto N, Katakami N, Atagi S et al. A Phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib or gefitinib [abstract 7524]. Presented at: Annual Meeting of the American Society of Clinical Oncology. Chicago, IL, USA, 4-8 June 2011.
70. Yap TA, Vidal L, Adam J et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J. Clin. Oncol. 28(25), 3965-3972 (2010).
71. Seiwert TY, Fayette J, DelCampo JM et al. A randomized, open-label, Phase II study of afatinib (BIBW 2992) versus cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck [abstract PP3.4]. Presented at: Proceedings of the 3rd Trends in Head and Neck Oncology. Rome, Italy, 3-5 November 2011.
72. Engelman JA, Zejnullahu K, Gale CM et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 67(24), 11924-11932 (2007).
73. Jänne PA, Boss DS, Camidge DR et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin. Cancer Res. 17(5), 1131-1139 (2011).
74. Siu LL, Hotte SJ, Laurie SA et al. Phase II trial of the irreversible oral pan-human EGF receptor (HER) inhibitor PF- 00299804 (PF) as first-line treatment in recurrent and/or metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). J. Clin. Oncol. 29, Abstract 5561 (2011).
75. Fakhry C, Westra WH, Li S et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J. Natl Cancer Inst. 100(4), 261-269 (2008). (Pubitemid 351480538)
76. Worden FP, Kumar B, Lee JS et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J. Clin. Oncol. 26(19), 3138-3146 (2008).
77. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J. Clin. Oncol. 27(12), 1992-1998 (2009).
78. Hong A, Dobbins T, Lee CS et al. Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer. Eur. J. Cancer 46(11), 2088-2096 (2010).
79. Chau NG, Perez-Ordonez B, Zhang K et al. The association between EGFR variant III, HPV, p16, c-MET, EGFR gene copy number and response to EGFR inhibitors in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Head Neck Oncol. 3, 11 (2011).
80. Psyrri A, Ghebremichael MS, Pectasides E et al. p16 protein status and response to treatment in a prospective clinical trial (ECOG 2303) of patients with head and neck squamous cell carcinoma (HNSCC). J. Clin. Oncol. 29, Abstract e16032 (2011).
81. Pajares B, Trigo Perez JM, Toledo MD et al. Human papillomavirus (HPV)- related head and neck squamous cell carcinoma (HNSCC) and outcome after treatment with epidermal growth factor receptor inhibitors (EGFR inhib) plus radiotherapy (RT) versus conventional chemotherapy (CT) plus RT. J. Clin. Oncol. 29, Abstract 5528 (2011).
82. Thomas F, Rochaix P, Benlyazid A et al. Pilot study of neoadjuvant treatment with erlotinib in nonmetastatic head and neck squamous cell carcinoma. Clin. Cancer Res. 13(23), 7086-7092 (2007). (Pubitemid 350276892)
83. Chua DT, Wei WI, Wong MP, Sham JS, Nicholls J, Au GK. Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head Neck 30(7), 863-867 (2008). (Pubitemid 352008945)
84. Ma B, Hui EP, King A et al. A Phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein-Barr virus DNA as a biomarker of efficacy. Cancer Chemother. Pharmacol. 62(1), 59-64 (2008). (Pubitemid 351537846)