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T1 Age 2 13 54-year-old T2 Sex 14 19 woman T3 Disease_disorder 34 39 NSCLC E1 Disease_disorder:T3 T4 Detailed_description 25 33 stage IV R1 MODIFY Arg1:T4 Arg2:E1 T5 Medication 57 68 carboplatin E2 Medication:T5 T6 Medication 73 83 paclitaxel E3 Medication:T6 T8 Diagnostic_procedure 110 128 Molecular analysis E4 Diagnostic_procedure:T8 T9 Diagnostic_procedure 132 144 tumor tissue E5 Diagnostic_procedure:T9 R2 SUB_PROCEDURE Arg1:E5 Arg2:E4 T10 Detailed_description 149 160 unavailable R3 MODIFY Arg1:T10 Arg2:E4 T12 Personal_background 209 214 Asian T13 History 224 239 smoking history T14 Severity 216 223 minimal R4 MODIFY Arg1:T14 Arg2:T13 T16 Medication 387 396 erlotinib E7 Medication:T16 T17 Lab_value 398 404 150 mg R5 MODIFY Arg1:T17 Arg2:T15 T18 Detailed_description 362 370 standard R7 MODIFY Arg1:T18 Arg2:T15 R8 BEFORE Arg1:E1 Arg2:E2 * OVERLAP E2 E3 E4 T19 Coreference 410 421 her disease E9 Coreference:T19 T20 Date 433 458 Twenty-eight months later E10 Date:T20 T21 Medication 487 496 erlotinib E11 Medication:T21 T22 Coreference 517 524 disease E12 Coreference:T22 T23 Detailed_description 525 537 systemically T24 Sign_symptom 4114 4122 survived E13 Sign_symptom:T24 T25 Date 4123 4171 14 months following the diagnosis of CNS disease E14 Date:T25 T26 Disease_disorder 4160 4171 CNS disease E15 Disease_disorder:T26 * OVERLAP E13 E14 T27 Date 3959 3974 One month later E16 Date:T27 T28 Medication 4032 4041 cetixumab E17 Medication:T28 T29 Medication 4046 4055 erlotinib E18 Medication:T29 T30 Lab_value 4095 4101 100 mg T31 Dosage 4085 4093;4103 4108 low dose daily R13 MODIFY Arg1:T30 Arg2:T31 T33 Dosage 3933 3947 1500 mg weekly T35 Medication 3948 3957 erlotinib E19 Medication:T35 R14 MODIFY Arg1:T33 Arg2:E19 R16 MODIFY Arg1:T31 Arg2:E18 A3 TREND E18 DEC R18 BEFORE Arg1:E19 Arg2:E16 T36 Disease_disorder 3988 4010 intra-thoracic disease E20 Disease_disorder:T36 T37 Detailed_description 3976 3987 progressive R19 MODIFY Arg1:T37 Arg2:E20 * OVERLAP E16 E20 R20 BEFORE Arg1:E20 Arg2:E17 * OVERLAP E17 E18 R21 BEFORE Arg1:E18 Arg2:E13 T38 Diagnostic_procedure 256 265 histology E21 Diagnostic_procedure:T38 T39 Detailed_description 241 255 non-small cell R22 MODIFY Arg1:T39 Arg2:E21 T40 Coreference 277 288 her disease E22 Coreference:T40 R23 IDENTICAL Arg1:E22 Arg2:E1 A4 POLARITY E4 NEG T47 History 256 265 histology T48 Diagnostic_procedure 302 326 EGFR TKI sensitive cells E23 Diagnostic_procedure:T48 R24 MODIFY Arg1:E23 Arg2:E22 R25 BEFORE Arg1:E23 Arg2:E7 R26 IDENTICAL Arg1:E12 Arg2:E9 T53 Detailed_description 502 513 progression R27 MODIFY Arg1:T53 Arg2:E12 * OVERLAP E11 E12 T54 Medication 593 615 angiogenesis inhibitor E24 Medication:T54 T55 Detailed_description 580 592 experimental R28 MODIFY Arg1:T55 Arg2:E24 T56 Medication 631 641 pemetrexed E25 Medication:T56 T57 Coreference 654 677 standard dose erlotinib E26 Coreference:T57 * OVERLAP E25 E26 T60 Date 703 718 11 months later E27 Date:T60 T61 Coreference 720 731 her disease E28 Coreference:T61 R29 IDENTICAL Arg1:E28 Arg2:E12 T62 Detailed_description 738 748 progressed R30 MODIFY Arg1:T62 Arg2:E28 * OVERLAP E28 E27 E30 R31 BEFORE Arg1:E26 Arg2:E27 T67 Other_event 473 483 resistance E29 Other_event:T67 * OVERLAP E10 E29 R32 MODIFY Arg1:E11 Arg2:E29 R33 BEFORE Arg1:E12 Arg2:E24 R34 BEFORE Arg1:E24 Arg2:E25 T68 Diagnostic_procedure 773 779 biopsy E30 Diagnostic_procedure:T68 T69 Diagnostic_procedure 887 904 Direct sequencing E31 Diagnostic_procedure:T69 T70 Diagnostic_procedure 950 954 EGFR E32 Diagnostic_procedure:T70 T71 Detailed_description 933 946 kinase domain R35 MODIFY Arg1:T71 Arg2:E32 T72 Diagnostic_procedure 968 982 L858R mutation E33 Diagnostic_procedure:T72 R36 SUB_PROCEDURE Arg1:E33 Arg2:E32 R37 SUB_PROCEDURE Arg1:E32 Arg2:E31 T73 Diagnostic_procedure 1058 1072 T790M mutation E34 Diagnostic_procedure:T73 T74 Biological_structure 750 753 DNA R38 MODIFY Arg1:T74 Arg2:E30 T75 Disease_disorder 802 808 lesion E35 Disease_disorder:T75 T76 Biological_structure 797 801 lung T77 Detailed_description 785 796 progressing R39 MODIFY Arg1:T76 Arg2:E35 R40 MODIFY Arg1:T77 Arg2:E35 T78 Diagnostic_procedure 867 881 EGFR mutations E36 Diagnostic_procedure:T78 T79 Sign_symptom 1150 1159 headaches E37 Sign_symptom:T79 T80 Disease_disorder 1207 1217 metastases E38 Disease_disorder:T80 T81 Biological_structure 1203 1206 CNS R41 MODIFY Arg1:T81 Arg2:E38 A5 POLARITY E38 MAYBE_POS T82 Diagnostic_procedure 1235 1242 imaging E39 Diagnostic_procedure:T82 T83 Lab_value 1226 1234 negative R42 MODIFY Arg1:T83 Arg2:E39 A6 POLARITY E39 NEG T84 Detailed_description 908 919 exons 18–21 R43 MODIFY Arg1:T84 Arg2:T71 T85 Detailed_description 999 1019 EGFR TKI sensitivity R44 MODIFY Arg1:T85 Arg2:E33 T86 Detailed_description 1089 1117 acquired EGFR TKI resistance R45 MODIFY Arg1:T86 Arg2:E34 T87 Therapeutic_procedure 1270 1285 lumbar puncture E40 Therapeutic_procedure:T87 A7 POLARITY E40 NEG T88 Medication 1309 1321 temozolomide E41 Medication:T88 T89 Detailed_description 1301 1308 empiric R46 MODIFY Arg1:T89 Arg2:E41 R47 MODIFY Arg1:T23 Arg2:E12 R50 MODIFY Arg1:E35 Arg2:E30 T90 Detailed_description 1327 1340 standard dose T92 Medication 1341 1350 erlotinib E6 Medication:T92 T93 Dosage 1352 1364 150 mg daily T91 Disease_disorder 1379 1390 CNS disease E42 Disease_disorder:T91 A8 POLARITY E42 MAYBE_POS T94 Time 1396 1411 after one cycle E43 Time:T94 T95 Sign_symptom 1416 1425 headaches E44 Sign_symptom:T95 T96 Lab_value 1426 1434 worsened R51 MODIFY Arg1:T96 Arg2:E44 T97 Sign_symptom 1454 1460 nausea E45 Sign_symptom:T97 T98 Sign_symptom 1465 1473 vomiting E46 Sign_symptom:T98 T99 Disease_disorder 1489 1503 CNS metastases E47 Disease_disorder:T99 T100 Diagnostic_procedure 1527 1548 intracranial pressure E48 Diagnostic_procedure:T100 T101 Lab_value 1520 1526 raised R52 MODIFY Arg1:T101 Arg2:E48 T102 Diagnostic_procedure 1550 1576 Magnetic resonance imaging E49 Diagnostic_procedure:T102 T103 Diagnostic_procedure 1577 1582 (MRI) E50 Diagnostic_procedure:T103 R53 IDENTICAL Arg1:E50 Arg2:E49 T104 Biological_structure 1590 1595 brain T105 Diagnostic_procedure 1637 1649 CSF cytology E51 Diagnostic_procedure:T105 R54 MODIFY Arg1:T104 Arg2:E50 R55 SUB_PROCEDURE Arg1:E51 Arg2:E50 T106 Disease_disorder 1613 1615 LM E52 Disease_disorder:T106 T107 Biological_structure 1685 1688 DNA T108 Diagnostic_procedure 1673 1683 sequencing E53 Diagnostic_procedure:T108 T109 Detailed_description 1666 1672 direct R56 MODIFY Arg1:T109 Arg2:E53 T110 Diagnostic_procedure 1694 1703 CSF cells E54 Diagnostic_procedure:T110 T111 Diagnostic_procedure 1713 1718 L858R E55 Diagnostic_procedure:T111 T112 Diagnostic_procedure 1730 1750 EGFR TKI sensitivity E56 Diagnostic_procedure:T112 T113 Diagnostic_procedure 1783 1808 T790M resistance mutation E57 Diagnostic_procedure:T113 T114 Diagnostic_procedure 1850 1855 T790M E58 Diagnostic_procedure:T114 A9 POLARITY E58 NEG T115 Lab_value 1860 1868 negative R57 MODIFY Arg1:T115 Arg2:E58 A10 POLARITY E56 MAYBE_POS A11 POLARITY E57 MAYBE_NEG T116 Coreference 1872 1883 this sample E59 Coreference:T116 R58 IDENTICAL Arg1:E59 Arg2:E54 T117 Diagnostic_procedure 1948 1953 assay E60 Diagnostic_procedure:T117 T118 Lab_value 1900 1914 more sensitive T119 Detailed_description 1915 1937 fluorescence detection T120 Detailed_description 1938 1947 PCR-based R59 MODIFY Arg1:T120 Arg2:E60 R60 MODIFY Arg1:T119 Arg2:E60 R61 MODIFY Arg1:T118 Arg2:E60 T121 Diagnostic_procedure 1980 2024 PCR restriction fragment length polymorphism E61 Diagnostic_procedure:T121 T122 Coreference 2038 2068 the specific missense mutation E62 Coreference:T122 T123 Coreference 2120 2131 That result E63 Coreference:T123 A12 POLARITY E63 NEG T124 Lab_value 2141 2149 negative R62 MODIFY Arg1:T124 Arg2:E63 T125 Diagnostic_procedure 2163 2177 wild type peak E64 Diagnostic_procedure:T125 A13 POLARITY E64 POS R63 IDENTICAL Arg1:E63 Arg2:E60 R64 SUB_PROCEDURE Arg1:E62 Arg2:E61 R65 IDENTICAL Arg1:E62 Arg2:E57 T155 Diagnostic_procedure 3025 3049 Pharmacokinetic analysis E76 Diagnostic_procedure:T155 T156 Biological_structure 3053 3056 CSF R81 MODIFY Arg1:T156 Arg2:E76 T157 Subject 3062 3077 another patient T158 Disease_disorder 3089 3091 LM E77 Disease_disorder:T158 T159 Disease_disorder 3083 3088 NSCLC E78 Disease_disorder:T159 R82 MODIFY Arg1:E78 Arg2:E77 T160 Dosage 3117 3124;3135 3141 1500 mg weekly T162 Medication 3125 3134 erlotinib E79 Medication:T162 R88 MODIFY Arg1:T160 Arg2:E79 R90 MODIFY Arg1:T93 Arg2:T90 R91 MODIFY Arg1:T90 Arg2:E6 T165 Lab_value 3186 3195 11,300 nM T166 Diagnostic_procedure 3157 3182 peak plasma concentration E80 Diagnostic_procedure:T166 T169 Lab_value 3235 3241 130 nM T170 Diagnostic_procedure 3214 3231 CSF concentration E81 Diagnostic_procedure:T170 R75 MODIFY Arg1:T169 Arg2:E81 R92 MODIFY Arg1:T165 Arg2:E80 T172 Detailed_description 3333 3351 exceeding the IC50 R93 MODIFY Arg1:T172 Arg2:T169 T178 Dosage 3458 3474 high-dose weekly T179 Medication 3475 3484 erlotinib E87 Medication:T179 T180 Lab_value 3488 3495 1000 mg T181 Lab_value 3501 3508 1200 mg R96 MODIFY Arg1:T178 Arg2:E87 R98 MODIFY Arg1:T180 Arg2:T178 R99 MODIFY Arg1:T181 Arg2:T178 R100 MODIFY Arg1:T178 Arg2:E87 T182 Sign_symptom 3521 3527 nausea E88 Sign_symptom:T182 T183 Detailed_description 3510 3520 persistent R102 MODIFY Arg1:T183 Arg2:E88 T184 Diagnostic_procedure 3552 3576 Pharmacokinetic analysis E89 Diagnostic_procedure:T184 A15 POLARITY E89 NEG T186 Disease_disorder 3758 3771 hydrocephalus E91 Disease_disorder:T186 T187 Sign_symptom 3787 3795 symptoms E92 Sign_symptom:T187 T188 Detailed_description 3776 3786 persistent R104 MODIFY Arg1:T188 Arg2:E92 T189 Diagnostic_procedure 3819 3840 intracranial pressure E93 Diagnostic_procedure:T189 T190 Therapeutic_procedure 3850 3858 VP shunt E94 Therapeutic_procedure:T190 T191 Lab_value 3809 3818 increased R105 MODIFY Arg1:T191 Arg2:E93 T192 Therapeutic_procedure 3875 3892 radiation therapy E95 Therapeutic_procedure:T192 T193 Biological_structure 3863 3874 whole-brain R106 MODIFY Arg1:T193 Arg2:E95 T7 Detailed_description 84 108 without disease response R9 MODIFY Arg1:T7 Arg2:E2 R10 MODIFY Arg1:T7 Arg2:E3 A2 POLARITY E23 MAYBE_POS * OVERLAP E5 E23 R11 IDENTICAL Arg1:E9 Arg2:E22 R12 BEFORE Arg1:E7 Arg2:E9 T11 Detailed_description 422 431 responded R107 MODIFY Arg1:T11 Arg2:E9 R108 BEFORE Arg1:E9 Arg2:E10 #1 AnnotatorNotes E29 Not sure how to label drug resistance R109 SUB_PROCEDURE Arg1:E36 Arg2:E30 R110 SUB_PROCEDURE Arg1:E31 Arg2:E36 R111 SUB_PROCEDURE Arg1:E34 Arg2:E8 T41 Coreference 1033 1035 It E8 Coreference:T41 R112 IDENTICAL Arg1:E8 Arg2:E31 * OVERLAP E34 E37 E38 E39 E40 E41 E6 E42 R113 BEFORE Arg1:E42 Arg2:E43 * OVERLAP E43 E44 E45 E46 E47 A1 POLARITY E47 MAYBE_POS R114 MODIFY Arg1:E48 Arg2:E47 * OVERLAP E48 E49 R115 MODIFY Arg1:E52 Arg2:E50 R116 MODIFY Arg1:E52 Arg2:E51 * OVERLAP E51 E53 R117 MODIFY Arg1:T107 Arg2:E54 R118 SUB_PROCEDURE Arg1:E54 Arg2:E53 R119 SUB_PROCEDURE Arg1:E55 Arg2:E54 R120 SUB_PROCEDURE Arg1:E56 Arg2:E55 R121 SUB_PROCEDURE Arg1:E57 Arg2:E54 * OVERLAP E57 E58 E60 R122 SUB_PROCEDURE Arg1:E61 Arg2:E60 * OVERLAP E62 E63 R123 SUB_PROCEDURE Arg1:E64 Arg2:E63 R66 MODIFY Arg1:T157 Arg2:E76 R67 MODIFY Arg1:E77 Arg2:T157 * OVERLAP E77 E79 E80 E81 * OVERLAP E64 E76 R68 BEFORE Arg1:E81 Arg2:E87 * OVERLAP E87 E88 E89 T42 Date 3613 3626 After 1 month E65 Date:T42 R69 BEFORE Arg1:E89 Arg2:E65 T43 Diagnostic_procedure 3684 3687 MRI E66 Diagnostic_procedure:T43 T44 Biological_structure 3678 3683 brain R70 MODIFY Arg1:T44 Arg2:E66 T45 Date 3701 3715 after 2 months E67 Date:T45 T46 Biological_structure 3723 3735 cauda equina R71 BEFORE Arg1:E66 Arg2:E67 T49 Disease_disorder 3672 3674 LM E68 Disease_disorder:T49 T50 Diagnostic_procedure 3639 3668 partial radiographic response E69 Diagnostic_procedure:T50 R72 MODIFY Arg1:E68 Arg2:E69 * OVERLAP E65 E69 R73 SUB_PROCEDURE Arg1:E69 Arg2:E66 * OVERLAP E67 E91 E66 E92 E93 R74 MODIFY Arg1:T46 Arg2:E66 R76 BEFORE Arg1:E93 Arg2:E94 * OVERLAP E94 E95 R77 BEFORE Arg1:E95 Arg2:E19 T15 Dosage 371 383 daily dosing R6 MODIFY Arg1:T15 Arg2:E7 R48 IDENTICAL Arg1:E26 Arg2:E7