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Nicolas Pécuchet, Eleonora Zonta, Audrey Didelot, Pierre Combe, Constance Thibault, Laure Gibault, Camille Lours, Yves Rozenholc, Valérie Taly, Pierre Laurent-Puig, Hélène Blons, Elizabeth Fabre
Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study
www.plosmedicine.org
www.plosmedicine.org
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3.3222 0 Td
(and)Tj
/F14 1 Tf
1.7291 0 Td
[()14()]TJ
/F8 1 Tf
(\))Tj
-33.783 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
1.5987 0 Td
(Molecular)Tj
4.2916 0 Td
(testing)Tj
2.8857 0 Td
(is)Tj
0.8447 0 Td
(routinely)Tj
3.8664 0 Td
(performed)Tj
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(on)Tj
1.2756 0 Td
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(extracted)Tj
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(tissue,)Tj
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(i.e.,)Tj
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(solid)Tj
-34.7128 -1.2983 Td
(biopsy,)Tj
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(and)Tj
1.7348 0 Td
(more)Tj
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(recently)Tj
3.4072 0 Td
(on)Tj
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(circulating)Tj
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(cell-free)Tj
3.4129 0 Td
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2.6022 0 Td
(i.e.,)Tj
1.5874 0 Td
(liquid)Tj
2.5625 0 Td
(biopsy)Tj
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([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(].)Tj
1.5987 0 Td
(Circulating)Tj
-30.9087 -1.2982 Td
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2.3754 0 Td
(may)Tj
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(facilitate)Tj
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(temporal)Tj
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(tumor)Tj
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(heterogeneity)Tj
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([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(],)Tj
2.3017 0 Td
(the)Tj
1.4626 0 Td
(characteri-)Tj
-33.2671 -1.304 Td
(zation)Tj
2.6872 0 Td
(of)Tj
1.0148 0 Td
(genetic)Tj
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(changes)Tj
3.4073 0 Td
(under)Tj
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(treatment,)Tj
4.3596 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
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(identification)Tj
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(of)Tj
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(secondary)Tj
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(resistance)Tj
-31.2262 -1.2982 Td
(mechanisms)Tj
5.2043 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
2.3017 0 Td
(It)Tj
0.8561 0 Td
(is)Tj
0.8504 0 Td
(also)Tj
1.7688 0 Td
(a)Tj
0.652 0 Td
(good)Tj
2.228 0 Td
(candidate)Tj
4.1045 0 Td
(for)Tj
1.389 0 Td
(early)Tj
2.1486 0 Td
(evaluation)Tj
4.3597 0 Td
(of)Tj
1.0148 0 Td
(treatment)Tj
4.1329 0 Td
(efficacy)Tj
3.2258 0 Td
(because)Tj
-34.2366 -1.2983 Td
(of)Tj
1.0147 0 Td
(its)Tj
1.1452 0 Td
(rapid)Tj
2.3358 0 Td
(clearance)Tj
3.9514 0 Td
(from)Tj
2.2054 0 Td
(plasma)Tj
3.033 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(].)Tj
-12.4893 -1.3039 Td
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1.1111 0 Td
(lung)Tj
2.007 0 Td
(cancer,)Tj
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(circulating)Tj
4.49 0 Td
(tumor)Tj
2.744 0 Td
(DNA)Tj
2.3754 0 Td
(\(ctDNA\))Tj
3.7814 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(validated)Tj
3.8324 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(surrogate)Tj
3.9798 0 Td
(material)Tj
-33.9248 -1.2983 Td
(to)Tj
1.0261 0 Td
(detect)Tj
2.6135 0 Td
(mutations)Tj
4.2803 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(gene)Tj
2.0806 0 Td
(encoding)Tj
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(epidermal)Tj
4.252 0 Td
(growth)Tj
3.0727 0 Td
(factor)Tj
2.5455 0 Td
(receptor)Tj
3.5546 0 Td
(\()Tj
/F14 1 Tf
[()]TJ
/F8 1 Tf
(\))Tj
3.2315 0 Td
(at)Tj
0.9524 0 Td
(diagno-)Tj
-34.0438 -1.2982 Td
(sis)Tj
1.2075 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(])Tj
3.3222 0 Td
(and)Tj
1.7291 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2939 0 Td
(secondary)Tj
/F14 1 Tf
4.2689 0 Td
[()]TJ
/F8 1 Tf
2.5512 0 Td
(mutations,)Tj
4.5071 0 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(p.T790M)Tj
3.8948 0 Td
(or)Tj
1.0998 0 Td
(p.C797S,)Tj
3.7531 0 Td
(at)Tj
0.9524 0 Td
(relapse)Tj
-34.6788 -1.3039 Td
(in)Tj
1.0318 0 Td
(patients)Tj
3.3732 0 Td
(treated)Tj
2.9933 0 Td
(with)Tj
1.9956 0 Td
(EGFR)Tj
2.6589 0 Td
(inhibitors)Tj
4.1385 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
3.549 0 Td
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1.7801 0 Td
(prognostic)Tj
4.4844 0 Td
(value)Tj
2.3074 0 Td
(of)Tj
1.0148 0 Td
(ctDNA)Tj
3.1011 0 Td
(has)Tj
1.542 0 Td
(been)Tj
-33.9701 -1.2983 Td
(investigated)Tj
4.9889 0 Td
(in)Tj
1.0318 0 Td
(different)Tj
3.6567 0 Td
(cancer)Tj
2.8459 0 Td
(types)Tj
2.2734 0 Td
(and)Tj
1.7348 0 Td
(is)Tj
0.8447 0 Td
(becoming)Tj
4.1839 0 Td
(an)Tj
1.2019 0 Td
(important)Tj
4.2803 0 Td
(topic)Tj
2.2337 0 Td
(in)Tj
1.0375 0 Td
(lung)Tj
2.0069 0 Td
(cancer.)Tj
3.067 0 Td
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-35.3874 -1.2983 Td
(technical)Tj
3.8097 0 Td
(challenge)Tj
3.9571 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
1.6781 0 Td
(research)Tj
3.5546 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0205 0 Td
(detect)Tj
2.6192 0 Td
(low)Tj
1.6554 0 Td
(concentrations)Tj
6.1795 0 Td
(of)Tj
1.0148 0 Td
(ctDNA,)Tj
3.3222 0 Td
(as)Tj
1.0148 0 Td
(found)Tj
2.6192 0 Td
(in)Tj
1.0375 0 Td
(lung)Tj
-35.3478 -1.2982 Td
(cancer,)Tj
3.067 0 Td
(and)Tj
1.7291 0 Td
(in)Tj
1.0375 0 Td
(clinical)Tj
3.0784 0 Td
(situations)Tj
4.0876 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(presence)Tj
3.7134 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(low)Tj
1.6554 0 Td
(tumor)Tj
2.744 0 Td
(burden.)Tj
3.3505 0 Td
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3.2371 0 Td
(by)Tj
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(analy-)Tj
-35.0983 -1.304 Td
(sis)Tj
1.2075 0 Td
(of)Tj
1.0148 0 Td
(mutations,)Tj
4.5071 0 Td
(ctDNA)Tj
3.101 0 Td
(was)Tj
1.6951 0 Td
(identified)Tj
4.0592 0 Td
(in)Tj
1.0375 0 Td
(only)Tj
1.9729 0 Td
(62%)Tj
1.9332 0 Td
(of)Tj
/F14 1 Tf
1.0148 0 Td
[()]TJ
/F8 1 Tf
(-mutated)Tj
6.2305 0 Td
(lung)Tj
2.0069 0 Td
(cancer)Tj
2.8403 0 Td
(patients)Tj
-32.6208 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(],)Tj
2.0749 0 Td
(as)Tj
1.0148 0 Td
(compared)Tj
4.2463 0 Td
(to)Tj
1.0261 0 Td
(92%)Tj
1.9275 0 Td
(of)Tj
/F14 1 Tf
1.0148 0 Td
[()-16()22()]TJ
/F8 1 Tf
(-mutated)Tj
6.2362 0 Td
(colon-cancer)Tj
5.4312 0 Td
(patients)Tj
3.3675 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(].)Tj
2.075 0 Td
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1.3379 0 Td
(accurately)Tj
4.2576 0 Td
(detect)Tj
-34.0098 -1.2983 Td
(ctDNA,)Tj
3.3221 0 Td
(ultra-sensitive)Tj
5.8507 0 Td
(methods)Tj
3.685 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(digital)Tj
2.7269 0 Td
(PCR)Tj
2.0636 0 Td
(\(dPCR\))Tj
3.2712 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(])Tj
3.0274 0 Td
(or)Tj
1.0998 0 Td
(optimized)Tj
4.2576 0 Td
(ultra-deep)Tj
-32.3827 -1.3039 Td
(next-generation)Tj
6.5933 0 Td
(sequencing)Tj
4.7168 0 Td
(\(NGS\))Tj
2.8233 0 Td
(are)Tj
1.4513 0 Td
(required)Tj
3.6397 0 Td
([)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(].)Tj
3.5433 0 Td
(Two)Tj
2.0239 0 Td
(issues)Tj
2.5172 0 Td
(have)Tj
2.0636 0 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1509 0 Td
(considered:)Tj
4.8245 0 Td
(\(1\))Tj
-36.3739 -1.2983 Td
(plasma)Tj
3.033 0 Td
(contains)Tj
3.6056 0 Td
(low)Tj
1.6555 0 Td
(concentrations)Tj
6.1795 0 Td
(of)Tj
1.0148 0 Td
(cell-free)Tj
3.4185 0 Td
(DNA,)Tj
2.6022 0 Td
(and)Tj
1.7291 0 Td
(\(2\))Tj
1.3777 0 Td
(ctDNA)Tj
3.0954 0 Td
(is)Tj
0.8504 0 Td
(often)Tj
2.2847 0 Td
(present)Tj
3.1634 0 Td
(at)Tj
0.9524 0 Td
(a)Tj
0.652 0 Td
(low)Tj
-35.6142 -1.2982 Td
(allelic)Tj
2.5058 0 Td
(ratio.)Tj
2.3244 0 Td
(The)Tj
1.7801 0 Td
(main)Tj
2.2904 0 Td
(interest)Tj
3.2088 0 Td
(in)Tj
1.0375 0 Td
(NGS)Tj
2.1486 0 Td
(is)Tj
0.8447 0 Td
(in)Tj
1.0375 0 Td
(allowing)Tj
3.617 0 Td
(a)Tj
0.6576 0 Td
(broad)Tj
2.5625 0 Td
(molecular)Tj
4.2236 0 Td
(screen)Tj
2.7723 0 Td
(using)Tj
2.3867 0 Td
(moderate)Tj
-33.3975 -1.304 Td
(amounts)Tj
3.7133 0 Td
(of)Tj
1.0148 0 Td
(template)Tj
3.685 0 Td
(DNA.)Tj
2.6022 0 Td
(Such)Tj
2.1713 0 Td
(an)Tj
1.2019 0 Td
(approach)Tj
3.9515 0 Td
(is)Tj
0.8504 0 Td
(well)Tj
1.8198 0 Td
(adapted)Tj
3.3846 0 Td
(to)Tj
1.0204 0 Td
(the)Tj
1.474 0 Td
(heterogeneous)Tj
6.0264 0 Td
(molecular)Tj
-32.9156 -1.2982 Td
(mechanisms)Tj
5.2043 0 Td
(driving)Tj
3.1238 0 Td
(lung)Tj
2.0069 0 Td
(carcinogenesis,)Tj
6.2702 0 Td
(tumor)Tj
2.7439 0 Td
(progression,)Tj
5.142 0 Td
(and)Tj
1.7348 0 Td
(acquired)Tj
3.7021 0 Td
(resistance)Tj
4.1272 0 Td
(to)Tj
1.0261 0 Td
(ther-)Tj
-35.0813 -1.2983 Td
(apy.)Tj
1.8481 0 Td
(NGS)Tj
2.1487 0 Td
(will)Tj
1.6667 0 Td
(also)Tj
1.7632 0 Td
(allow)Tj
2.3414 0 Td
(a)Tj
0.6519 0 Td
(wide)Tj
2.1203 0 Td
(genetic)Tj
3.0728 0 Td
(analysis)Tj
3.3278 0 Td
(suitable)Tj
3.2825 0 Td
(for)Tj
1.389 0 Td
(unselected)Tj
4.422 0 Td
(patient)Tj
3.0047 0 Td
(screening.)Tj
-31.0391 -1.3039 Td
(Moreover,)Tj
4.3936 0 Td
(in)Tj
1.0375 0 Td
(some)Tj
2.3301 0 Td
(specific)Tj
3.1918 0 Td
(cases,)Tj
2.4491 0 Td
(it)Tj
0.7823 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1509 0 Td
(used)Tj
2.0579 0 Td
(to)Tj
1.0261 0 Td
(assess)Tj
2.5229 0 Td
(the)Tj
1.4683 0 Td
(relative)Tj
3.1408 0 Td
(disposition)Tj
4.6488 0 Td
(of)Tj
1.0147 0 Td
(different)Tj
-32.8419 -1.2983 Td
(genetic)Tj
3.067 0 Td
(alterations,)Tj
4.6375 0 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
/F14 1 Tf
1.4683 0 Td
[()1()-4()]TJ
/F8 1 Tf
1.1906 0 Td
(or)Tj
/F14 1 Tf
1.0998 0 Td
[()7()20()16()]TJ
/F8 1 Tf
2.2224 0 Td
(positions)Tj
3.8551 0 Td
(of)Tj
/F14 1 Tf
1.0148 0 Td
[()]TJ
/F8 1 Tf
2.5455 0 Td
(p.C797S)Tj
3.5319 0 Td
(and)Tj
1.7291 0 Td
(p.T790M)Tj
3.8948 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(].)Tj
2.075 0 Td
(For)Tj
-35.4045 -1.2982 Td
(this)Tj
1.6724 0 Td
(purpose,)Tj
3.6737 0 Td
(we)Tj
1.3266 0 Td
(previously)Tj
4.3483 0 Td
(developed)Tj
4.2689 0 Td
(the)Tj
1.474 0 Td
(base-position)Tj
5.5672 0 Td
(error)Tj
2.2621 0 Td
(rate)Tj
1.7518 0 Td
(\(BPER\))Tj
3.2258 0 Td
(method,)Tj
3.5489 0 Td
(a)Tj
0.6577 0 Td
(bioinfor-)Tj
-33.7774 -1.2983 Td
(matics)Tj
2.8232 0 Td
(analytical)Tj
4.0082 0 Td
(pipeline)Tj
3.4299 0 Td
(dedicated)Tj
4.0705 0 Td
(to)Tj
1.0262 0 Td
(routine)Tj
3.1634 0 Td
(ctDNA)Tj
3.1011 0 Td
(testing)Tj
2.88 0 Td
(using)Tj
2.3867 0 Td
(ultra-deep)Tj
4.3427 0 Td
(targeted)Tj
3.4639 0 Td
(NGS)Tj
2.143 0 Td
(at)Tj
-36.8388 -1.3039 Td
(10,000)Tj
/F15 1 Tf
[()]TJ
/F8 1 Tf
3.3902 0 Td
(\(Ion)Tj
1.9559 0 Td
(Proton,)Tj
3.2371 0 Td
(Thermo)Tj
3.4809 0 Td
(Fisher)Tj
2.6986 0 Td
(Scientific\))Tj
4.2406 0 Td
([)Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(].)Tj
-17.8071 -1.2983 Td
(In)Tj
1.1111 0 Td
(the)Tj
1.4684 0 Td
(present)Tj
3.1634 0 Td
(prospective)Tj
4.7849 0 Td
(observational)Tj
5.5785 0 Td
(study,)Tj
2.6192 0 Td
(we)Tj
1.3266 0 Td
(tested)Tj
2.5512 0 Td
(the)Tj
1.4683 0 Td
(clinical)Tj
3.0784 0 Td
(utility)Tj
2.5795 0 Td
(of)Tj
1.0148 0 Td
(liquid)Tj
2.5625 0 Td
(biopsy)Tj
-34.503 -1.2982 Td
(in)Tj
1.0318 0 Td
(advanced)Tj
3.9968 0 Td
(or)Tj
1.0998 0 Td
(metastatic)Tj
4.2746 0 Td
(NSCLC)Tj
3.2995 0 Td
(patients)Tj
3.3676 0 Td
(\()Tj
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[()]TJ
/F8 1 Tf
1.0885 0 Td
(=)Tj
0.7993 0 Td
(256)Tj
1.6441 0 Td
(plasma)Tj
3.0331 0 Td
(samples)Tj
3.3845 0 Td
(from)Tj
2.2054 0 Td
(124)Tj
1.644 0 Td
(patients\).)Tj
-30.869 -1.304 Td
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3.6226 0 Td
(inclusion)Tj
3.9175 0 Td
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1.7007 0 Td
(not)Tj
1.5704 0 Td
(based)Tj
2.4775 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(existence)Tj
3.8551 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(defined)Tj
3.2258 0 Td
(tumor)Tj
2.7439 0 Td
(mutation)Tj
3.9231 0 Td
(such)Tj
2.058 0 Td
(as)Tj
/F14 1 Tf
1.0147 0 Td
[()]TJ
/F8 1 Tf
-34.52 -1.2982 Td
(or)Tj
/F14 1 Tf
1.0941 0 Td
[()-16()22()]TJ
/F8 1 Tf
(.)Tj
2.7893 0 Td
(Our)Tj
1.8652 0 Td
(primary)Tj
3.4582 0 Td
(objective)Tj
3.7757 0 Td
(was)Tj
1.7008 0 Td
(to)Tj
1.0262 0 Td
(evaluate)Tj
3.4639 0 Td
(the)Tj
1.4683 0 Td
(prognostic)Tj
4.4844 0 Td
(value)Tj
2.3074 0 Td
(of)Tj
1.0148 0 Td
(ctDNA)Tj
3.1011 0 Td
(positivity)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 134.7591 23.6976 re
W* n
q
134.7024 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 368.107 745.7952 cm
BT
/F0 1 Tf
1 TL
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