%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Francesca Tartari, Alessandro Conti, Roy Cerqueti
Assessing the relationship between toxicity and economic cost of oncological target agents: A systematic review of clinical trials
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 8 0 R/Annots 9 0 R/Contents 10 0 R/TrimBox[0 0 612 792]>>
endobj
9 0 obj
[11 0 R 12 0 R 13 0 R 14 0 R 15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R]
endobj
11 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref001)>>
endobj
12 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref002)>>
endobj
13 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref003)>>
endobj
14 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref004)>>
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref008)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref009)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref010)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref011)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref012)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref020)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref014)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref015)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref021)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref021)>>
endobj
25 0 obj
<>/Border[0 0 0]/A 26 0 R>>
endobj
26 0 obj
<>
endobj
10 0 obj
[27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R 39 0 R 40 0 R]
endobj
27 0 obj
<>stream
q
0.83 0.64 0.02 0 k
425.0835 667.3323 m
429.8457 667.3323 l
h
f*
477.411 654.3496 m
482.1732 654.3496 l
h
f*
263.3953 628.3276 m
268.1575 628.3276 l
h
f*
541.3039 537.3354 m
546.0661 537.3354 l
h
f*
551.2252 537.3354 m
555.9874 537.3354 l
h
f*
234.9921 485.348 m
239.7543 485.348 l
h
f*
528.8882 459.326 m
538.4126 459.326 l
h
f*
278.3055 407.3386 m
287.8299 407.3386 l
h
f*
407.2252 368.3339 m
416.6929 368.3339 l
h
f*
421.9087 368.3339 m
431.3764 368.3339 l
h
f*
462.3307 342.3118 m
471.8551 342.3118 l
h
f*
404.5606 277.3417 m
414.0283 277.3417 l
h
f*
506.6646 134.3055 m
516.189 134.3055 l
h
f*
535.1811 95.3008 m
544.6488 95.3008 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(the)Tj
1.4683 0 Td
(approval)Tj
3.702 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.474 0 Td
(US)Tj
1.4287 0 Td
(Food)Tj
2.2904 0 Td
(and)Tj
1.7291 0 Td
(Drug)Tj
2.3244 0 Td
(Administration)Tj
6.4176 0 Td
(\(FDA\))Tj
2.8459 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(target)Tj
2.5059 0 Td
(agents)Tj
2.7552 0 Td
(and)Tj
1.7291 0 Td
(of)Tj
1.0148 0 Td
(their)Tj
-35.3534 -1.3039 Td
(introduction)Tj
5.312 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4741 0 Td
(clinical)Tj
3.0727 0 Td
(practice.)Tj
-9.6944 -1.2982 Td
(The)Tj
1.7858 0 Td
(motivations)Tj
4.9833 0 Td
(for)Tj
1.3833 0 Td
(our)Tj
1.627 0 Td
(study)Tj
2.3925 0 Td
(are)Tj
1.4456 0 Td
(of)Tj
1.0148 0 Td
(economic)Tj
4.1386 0 Td
(and)Tj
1.7291 0 Td
(social)Tj
2.4604 0 Td
(nature.)Tj
3.0501 0 Td
(In)Tj
1.1112 0 Td
(fact,)Tj
1.8878 0 Td
(cancer)Tj
2.8403 0 Td
(is)Tj
0.8504 0 Td
(one)Tj
1.7008 0 Td
(of)Tj
-35.5972 -1.2983 Td
(the)Tj
1.4683 0 Td
(most)Tj
2.2053 0 Td
(costly)Tj
2.5115 0 Td
(health)Tj
2.6759 0 Td
(conditions)Tj
4.4787 0 Td
(to)Tj
1.0261 0 Td
(manage)Tj
3.3449 0 Td
(worldwide)Tj
4.456 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(].)Tj
1.5988 0 Td
(Anticancer)Tj
4.6431 0 Td
(agents)Tj
2.7552 0 Td
(have)Tj
2.058 0 Td
(repre-)Tj
-33.2218 -1.2983 Td
(sented)Tj
2.8006 0 Td
(the)Tj
1.4683 0 Td
(43%)Tj
1.9332 0 Td
(of)Tj
1.0148 0 Td
(new)Tj
1.8709 0 Td
(drugs)Tj
2.4774 0 Td
(approved)Tj
3.9685 0 Td
(by)Tj
1.1849 0 Td
(the)Tj
1.4683 0 Td
(FDA)Tj
2.1713 0 Td
(in)Tj
1.0319 0 Td
(the)Tj
1.4683 0 Td
(last)Tj
1.5647 0 Td
(decade)Tj
2.9764 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(].)Tj
1.6044 0 Td
(The)Tj
1.7801 0 Td
(increase)Tj
3.4696 0 Td
(of)Tj
1.0148 0 Td
(drug)Tj
-35.2684 -1.3039 Td
(spending)Tj
3.8777 0 Td
(in)Tj
1.0375 0 Td
(oncology)Tj
3.8778 0 Td
(is)Tj
0.8447 0 Td
(mainly)Tj
2.9934 0 Td
(due)Tj
1.7007 0 Td
(to)Tj
1.0205 0 Td
(the)Tj
1.474 0 Td
(recent)Tj
2.7042 0 Td
(introduction)Tj
5.3178 0 Td
(of)Tj
1.0148 0 Td
(new)Tj
1.8708 0 Td
(targeted)Tj
3.464 0 Td
(and)Tj
1.7291 0 Td
(immuno-)Tj
-32.927 -1.2982 Td
(therapy)Tj
3.2484 0 Td
(agents)Tj
2.7496 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(],)Tj
1.5988 0 Td
(which)Tj
2.6532 0 Td
(have)Tj
2.0579 0 Td
(improved)Tj
4.1102 0 Td
(the)Tj
1.4684 0 Td
(outcome)Tj
3.7247 0 Td
(of)Tj
1.0147 0 Td
(cancer)Tj
2.846 0 Td
(patients)Tj
3.3676 0 Td
(in)Tj
1.0374 0 Td
(terms)Tj
2.4945 0 Td
(of)Tj
1.0148 0 Td
(Overall)Tj
-33.3862 -1.2983 Td
(Survival)Tj
3.4525 0 Td
(\(OS\))Tj
2.1203 0 Td
(and)Tj
1.7292 0 Td
(Progression-Free)Tj
7.0582 0 Td
(Survival)Tj
3.4526 0 Td
(\(PFS\))Tj
2.4604 0 Td
(compared)Tj
4.2463 0 Td
(to)Tj
1.0261 0 Td
(conventional)Tj
5.4255 0 Td
(chemotherapy.)Tj
-30.9711 -1.3039 Td
(Although)Tj
4.0024 0 Td
(these)Tj
2.2564 0 Td
(agents)Tj
2.7496 0 Td
(are)Tj
1.4457 0 Td
(generally)Tj
3.838 0 Td
(associated)Tj
4.252 0 Td
(with)Tj
2.0012 0 Td
(a)Tj
0.652 0 Td
(lower)Tj
2.4548 0 Td
(rate)Tj
1.7461 0 Td
(of)Tj
1.0148 0 Td
(treatment)Tj
4.1329 0 Td
(D)Tj
0.9581 0 Td
(due)Tj
1.7008 0 Td
(to)Tj
1.0204 0 Td
(drug)Tj
-34.2252 -1.2983 Td
(toxicity,)Tj
3.4242 0 Td
(their)Tj
2.1089 0 Td
(impact)Tj
2.9821 0 Td
(on)Tj
1.2756 0 Td
(patients')Tj
3.5829 0 Td
(Quality)Tj
3.1918 0 Td
(of)Tj
1.0148 0 Td
(Life)Tj
1.7405 0 Td
(\(QoL\))Tj
2.6872 0 Td
(should)Tj
2.9197 0 Td
(not)Tj
1.576 0 Td
(be)Tj
1.1452 0 Td
(overlooked.)Tj
4.9096 0 Td
(Improving)Tj
-32.5585 -1.2983 Td
(patients')Tj
3.5829 0 Td
(QoL)Tj
2.0126 0 Td
(and)Tj
1.7291 0 Td
(their)Tj
2.109 0 Td
(compliance)Tj
4.8302 0 Td
(to)Tj
1.0261 0 Td
(treatments)Tj
4.4958 0 Td
(will)Tj
1.661 0 Td
(represent)Tj
3.9572 0 Td
(the)Tj
1.474 0 Td
(challenge)Tj
3.9571 0 Td
(for)Tj
1.3833 0 Td
(cancer)Tj
-32.2183 -1.3039 Td
(researchers)Tj
4.7111 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(future)Tj
2.6532 0 Td
(years.)Tj
2.4945 0 Td
(Indeed,)Tj
3.2315 0 Td
(by)Tj
1.1848 0 Td
(a)Tj
0.652 0 Td
(purely)Tj
2.7609 0 Td
(economic)Tj
4.1386 0 Td
(perspective,)Tj
4.9266 0 Td
(reducing)Tj
3.7757 0 Td
(the)Tj
1.4683 0 Td
(toxic)Tj
-34.503 -1.2982 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2507 0 Td
(treatments)Tj
4.4957 0 Td
(will)Tj
1.6667 0 Td
(allow)Tj
2.3358 0 Td
(to)Tj
1.0261 0 Td
(decrease)Tj
3.6056 0 Td
(the)Tj
1.4741 0 Td
(abstention)Tj
4.4106 0 Td
(from)Tj
2.2054 0 Td
(work)Tj
2.279 0 Td
(days)Tj
1.9956 0 Td
(and)Tj
1.7348 0 Td
(to)Tj
1.0205 0 Td
(increase)Tj
-34.2423 -1.2983 Td
(productivity,)Tj
5.3574 0 Td
(hence)Tj
2.5682 0 Td
(leading)Tj
3.1351 0 Td
(to)Tj
1.0204 0 Td
(a)Tj
0.6577 0 Td
(wider)Tj
2.4944 0 Td
(access)Tj
2.6419 0 Td
(to)Tj
1.0261 0 Td
(cures)Tj
2.3301 0 Td
(due)Tj
1.6951 0 Td
(to)Tj
1.0262 0 Td
(a)Tj
0.6576 0 Td
(better)Tj
2.5398 0 Td
(economic)Tj
4.1386 0 Td
(status)Tj
2.5001 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
-32.5925 -1.3039 Td
(This)Tj
1.9899 0 Td
(paper)Tj
2.4831 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1508 0 Td
(properly)Tj
3.6284 0 Td
(inserted)Tj
3.4412 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(frame)Tj
2.5568 0 Td
(of)Tj
1.0148 0 Td
(pharmacoeconomics,)Tj
8.759 0 Td
(which)Tj
2.6476 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.6519 0 Td
(scien-)Tj
-34.503 -1.2983 Td
(tific)Tj
1.7631 0 Td
(discipline)Tj
4.0705 0 Td
(related)Tj
2.9424 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4683 0 Td
(cost)Tj
1.8085 0 Td
(and)Tj
1.7348 0 Td
(the)Tj
1.4684 0 Td
(value)Tj
2.3073 0 Td
(of)Tj
1.0148 0 Td
(drugs)Tj
2.4718 0 Td
(and)Tj
1.7292 0 Td
(provides)Tj
3.651 0 Td
(suggestion)Tj
4.4447 0 Td
(for)Tj
1.3832 0 Td
(the)Tj
1.4684 0 Td
(opti-)Tj
-34.7525 -1.2982 Td
(mal)Tj
1.7177 0 Td
(allocation)Tj
4.1329 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(healh)Tj
2.381 0 Td
(care)Tj
1.8709 0 Td
(resources.)Tj
4.2179 0 Td
(This)Tj
1.9843 0 Td
(conceptualization)Tj
7.3076 0 Td
(was)Tj
1.6951 0 Td
(proposed)Tj
3.9515 0 Td
(by)Tj
1.1849 0 Td
(Townsend)Tj
-32.927 -1.2983 Td
(in)Tj
1.0318 0 Td
(1987)Tj
2.1259 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(],)Tj
1.5988 0 Td
(who)Tj
1.9388 0 Td
(identified)Tj
4.0592 0 Td
(the)Tj
1.4684 0 Td
(Pharmacoeconomics)Tj
8.5775 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.8652 0 Td
(description)Tj
4.7282 0 Td
(and)Tj
1.7348 0 Td
(the)Tj
1.4683 0 Td
(analysis)Tj
3.3279 0 Td
(of)Tj
-34.9396 -1.3039 Td
(costs)Tj
2.1713 0 Td
(of)Tj
1.0148 0 Td
(therapeutic)Tj
4.7281 0 Td
(approch)Tj
3.5206 0 Td
(substained)Tj
4.4731 0 Td
(by)Tj
1.1849 0 Td
(the)Tj
1.4683 0 Td
(Health)Tj
2.9197 0 Td
(System)Tj
3.05 0 Td
(and)Tj
1.7291 0 Td
(Society.)Tj
3.6907 0 Td
(However,)Tj
4.0762 0 Td
(the)Tj
1.4684 0 Td
(first)Tj
-35.4952 -1.2983 Td
(definition)Tj
4.1612 0 Td
(of)Tj
1.0148 0 Td
(Pharmacoeconomics)Tj
8.5776 0 Td
(dates)Tj
2.262 0 Td
(back)Tj
2.0806 0 Td
(to)Tj
1.0261 0 Td
(1977)Tj
2.126 0 Td
(when)Tj
2.4038 0 Td
(Weinstein)Tj
4.32 0 Td
(and)Tj
1.7291 0 Td
(Stason)Tj
2.8459 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(])Tj
1.8539 0 Td
(pub-)Tj
-34.401 -1.2983 Td
(lished)Tj
2.5738 0 Td
(a)Tj
0.652 0 Td
(paper)Tj
2.4831 0 Td
(dealing)Tj
3.1351 0 Td
(with)Tj
1.9956 0 Td
(economic)Tj
4.1385 0 Td
(analysis)Tj
3.3279 0 Td
(in)Tj
1.0375 0 Td
(health)Tj
2.6758 0 Td
(field.)Tj
-20.8231 -1.3039 Td
(On)Tj
1.5193 0 Td
(the)Tj
1.4684 0 Td
(current)Tj
3.1861 0 Td
(scenario)Tj
3.5546 0 Td
(of)Tj
1.0148 0 Td
(rapidly)Tj
3.0387 0 Td
(rising)Tj
2.5002 0 Td
(health)Tj
2.6759 0 Td
(care)Tj
1.8708 0 Td
(costs,)Tj
2.3981 0 Td
(pharmaeconomic)Tj
7.2453 0 Td
(techniques)Tj
4.5241 0 Td
(are)Tj
-36.1925 -1.2982 Td
(becoming)Tj
4.1782 0 Td
(increasingly)Tj
5.0343 0 Td
(relevant)Tj
3.4186 0 Td
(to)Tj
1.0261 0 Td
(analyze)Tj
3.1748 0 Td
(the)Tj
1.4683 0 Td
(cost-effectiveness)Tj
7.1433 0 Td
(and)Tj
1.7291 0 Td
(economic)Tj
4.1442 0 Td
(sustainability)Tj
-31.3169 -1.2983 Td
(of)Tj
1.0147 0 Td
(emerging)Tj
4.0025 0 Td
(drugs)Tj
2.4718 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(].)Tj
2.0807 0 Td
(Among)Tj
3.2428 0 Td
(such)Tj
2.0579 0 Td
(techniques,)Tj
4.7565 0 Td
(cluster)Tj
2.8687 0 Td
(analysis)Tj
3.3278 0 Td
(plays)Tj
2.2337 0 Td
(a)Tj
0.652 0 Td
(relevant)Tj
3.4242 0 Td
(role.)Tj
1.9899 0 Td
(In)Tj
1.1112 0 Td
(fact,)Tj
-35.2344 -1.3039 Td
(cluster)Tj
2.8686 0 Td
(analysis)Tj
3.3278 0 Td
(is)Tj
0.8504 0 Td
(used)Tj
2.058 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2938 0 Td
(groups)Tj
2.9707 0 Td
(of)Tj
1.0148 0 Td
(similar)Tj
2.9877 0 Td
(data)Tj
1.9106 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2755 0 Td
(selected)Tj
3.3506 0 Td
(variables)Tj
3.719 0 Td
(and)Tj
1.7291 0 Td
(is)Tj
0.8504 0 Td
(par-)Tj
-35.7049 -1.2983 Td
(ticularly)Tj
3.4865 0 Td
(suitable)Tj
3.2882 0 Td
(for)Tj
1.3833 0 Td
(their)Tj
2.109 0 Td
(comparison.)Tj
5.1987 0 Td
(The)Tj
1.7858 0 Td
(versatility)Tj
4.0932 0 Td
(of)Tj
1.0148 0 Td
(such)Tj
2.0636 0 Td
(a)Tj
0.652 0 Td
(statistical)Tj
3.9118 0 Td
(technique)Tj
4.1669 0 Td
(explains)Tj
-33.1538 -1.2983 Td
(also)Tj
1.7688 0 Td
(its)Tj
1.1451 0 Td
(popularity)Tj
4.3597 0 Td
(in)Tj
1.0375 0 Td
(many)Tj
2.4774 0 Td
(fields)Tj
2.3301 0 Td
(of)Tj
1.0148 0 Td
(applied)Tj
3.1521 0 Td
(science)Tj
3.0954 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
3.5433 0 Td
(Indeed,)Tj
3.2372 0 Td
(cluster)Tj
2.8686 0 Td
(analysis)Tj
3.3279 0 Td
(seems)Tj
2.6078 0 Td
(to)Tj
-35.9657 -1.2982 Td
(be)Tj
1.1508 0 Td
(appropiate)Tj
4.5071 0 Td
(for)Tj
1.3833 0 Td
(performing)Tj
4.8018 0 Td
(a)Tj
0.652 0 Td
(global)Tj
2.6249 0 Td
(study)Tj
2.3924 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(connection)Tj
4.7168 0 Td
(between)Tj
3.5263 0 Td
(drug)Tj
2.1146 0 Td
(effectiveness,)Tj
5.4255 0 Td
(tox-)Tj
-35.7786 -1.3039 Td
(icity)Tj
1.9275 0 Td
(and)Tj
1.7348 0 Td
(cost.)Tj
2.0353 0 Td
(In)Tj
1.1055 0 Td
(this)Tj
1.6724 0 Td
(context,)Tj
3.4129 0 Td
(it)Tj
0.7823 0 Td
(is)Tj
0.8504 0 Td
(worth)Tj
2.6079 0 Td
(mentioning)Tj
4.9152 0 Td
(Perrier)Tj
3.0047 0 Td
(et)Tj
0.9411 0 Td
(al)Tj
0.9014 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(],)Tj
2.075 0 Td
(who)Tj
1.9389 0 Td
(explored)Tj
3.702 0 Td
(the)Tj
1.474 0 Td
(trans-)Tj
-35.0813 -1.2983 Td
(ferability)Tj
3.7757 0 Td
(of)Tj
1.0148 0 Td
(health)Tj
2.6759 0 Td
(cost)Tj
1.8141 0 Td
(assessment)Tj
4.6091 0 Td
(between)Tj
3.5263 0 Td
(Italy)Tj
1.9956 0 Td
(and)Tj
1.7291 0 Td
(France.)Tj
3.1748 0 Td
(The)Tj
1.7801 0 Td
(authors)Tj
3.2485 0 Td
(constructed)Tj
4.9323 0 Td
(a)Tj
-34.2763 -1.2983 Td
(hierarchical)Tj
4.9379 0 Td
(structure)Tj
3.821 0 Td
(using)Tj
2.3868 0 Td
(cluster)Tj
2.8743 0 Td
(analysis)Tj
3.3279 0 Td
(and)Tj
1.7291 0 Td
(identified)Tj
4.0592 0 Td
(four)Tj
1.9105 0 Td
(different)Tj
3.6567 0 Td
(clusters)Tj
3.2315 0 Td
(based)Tj
2.4774 0 Td
(on)Tj
-34.4123 -1.3039 Td
(diagnosis,)Tj
4.1839 0 Td
(surgery,)Tj
3.4185 0 Td
(chemotherapy)Tj
5.9471 0 Td
(and)Tj
1.7291 0 Td
(follow-up.)Tj
4.32 0 Td
(Their)Tj
2.4207 0 Td
(findings)Tj
3.498 0 Td
(showed)Tj
3.2485 0 Td
(that)Tj
1.7801 0 Td
(a)Tj
0.652 0 Td
(high)Tj
2.0069 0 Td
(variability)Tj
-33.2048 -1.2982 Td
(was)Tj
1.6951 0 Td
(present)Tj
3.1634 0 Td
(between)Tj
3.5319 0 Td
(this)Tj
1.6725 0 Td
(two)Tj
1.7121 0 Td
(countries,)Tj
4.1726 0 Td
(suggesting)Tj
4.3993 0 Td
(a)Tj
0.6576 0 Td
(low)Tj
1.6555 0 Td
(transferability)Tj
5.7883 0 Td
(of)Tj
1.0148 0 Td
(cost)Tj
1.8141 0 Td
(evaluations)Tj
-31.2772 -1.2983 Td
(across)Tj
2.6758 0 Td
(Italy)Tj
1.9956 0 Td
(and)Tj
1.7291 0 Td
(France.)Tj
3.1748 0 Td
(Two)Tj
2.0183 0 Td
(years)Tj
2.2677 0 Td
(later,)Tj
2.2167 0 Td
(Liao)Tj
1.9672 0 Td
(et)Tj
0.9411 0 Td
(al.)Tj
1.1282 0 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(])Tj
1.8481 0 Td
(performed)Tj
4.4731 0 Td
(an)Tj
1.2019 0 Td
(observational)Tj
5.5785 0 Td
(study)Tj
2.3868 0 Td
(on)Tj
-35.6029 -1.3039 Td
(18,380)Tj
2.8232 0 Td
(patients)Tj
3.3676 0 Td
(with)Tj
1.9956 0 Td
(end-stage)Tj
4.0535 0 Td
(renal)Tj
2.245 0 Td
(disease)Tj
3.016 0 Td
(who)Tj
1.9389 0 Td
(initiated)Tj
3.5547 0 Td
(hemodialysis.)Tj
5.6409 0 Td
(By)Tj
1.2529 0 Td
(using)Tj
2.3867 0 Td
(K-means)Tj
-32.275 -1.2983 Td
(and)Tj
1.7291 0 Td
(hierarchical)Tj
4.9379 0 Td
(cluster)Tj
2.8686 0 Td
(analyses)Tj
3.4866 0 Td
(with)Tj
1.9956 0 Td
(either)Tj
2.5342 0 Td
(flexible)Tj
3.084 0 Td
(beta)Tj
1.8822 0 Td
(or)Tj
1.0999 0 Td
(Ward's)Tj
3.0954 0 Td
(methods,)Tj
3.9061 0 Td
(they)Tj
1.9275 0 Td
(identified)Tj
4.0592 0 Td
(4)Tj
-36.6063 -1.2983 Td
(clusters)Tj
3.2314 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(sample)Tj
3.0217 0 Td
(sizes)Tj
2.0466 0 Td
(and)Tj
1.7291 0 Td
(change)Tj
3.0444 0 Td
(of)Tj
1.0148 0 Td
(cost)Tj
1.8085 0 Td
(patterns,)Tj
3.6964 0 Td
(finding)Tj
3.1351 0 Td
(that)Tj
1.7745 0 Td
(higher)Tj
2.8062 0 Td
(costs)Tj
2.1714 0 Td
(were)Tj
2.1203 0 Td
(cor-)Tj
-35.3478 -1.3039 Td
(related)Tj
2.9423 0 Td
(with)Tj
1.9956 0 Td
(more)Tj
2.3414 0 Td
(increasing)Tj
4.3313 0 Td
(comorbidity)Tj
5.1703 0 Td
(scores.)Tj
-15.5847 -1.2982 Td
(In)Tj
-0.023 Tc
1.1111 0 Td
(our)Tj
1.5704 0 Td
(study)Tj
2.2961 0 Td
(we)Tj
1.2869 0 Td
(are)Tj
1.389 0 Td
(different)Tj
3.4866 0 Td
(from)Tj
2.1316 0 Td
(the)Tj
1.4116 0 Td
(quoted)Tj
2.897 0 Td
(papers)Tj
2.7326 0 Td
(since)Tj
2.1487 0 Td
(we)Tj
1.2869 0 Td
(first)Tj
1.7121 0 Td
(create)Tj
2.4775 0 Td
(a)Tj
0.6349 0 Td
(dataset)Tj
2.8687 0 Td
(containing)Tj
-32.6379 -1.2983 Td
(clinical)Tj
2.9139 0 Td
(and)Tj
1.6611 0 Td
(economic)Tj
3.9742 0 Td
(information)Tj
4.8585 0 Td
(about)Tj
2.3868 0 Td
(all)Tj
1.0828 0 Td
(the)Tj
1.4003 0 Td
(oncological)Tj
4.5751 0 Td
(target)Tj
2.3868 0 Td
(agents)Tj
2.6248 0 Td
(approved)Tj
3.8098 0 Td
(in)Tj
0.9864 0 Td
(clinical)Tj
2.914 0 Td
(prac-)Tj
-35.5745 -1.2983 Td
(tice.)Tj
1.7631 0 Td
(In)Tj
1.0715 0 Td
(this)Tj
1.593 0 Td
(respect,)Tj
3.1125 0 Td
(it)Tj
0.7483 0 Td
(is)Tj
0.8107 0 Td
(important)Tj
4.1102 0 Td
(to)Tj
0.9865 0 Td
(recall)Tj
2.2507 0 Td
(that)Tj
1.7064 0 Td
(a)Tj
0.635 0 Td
(target)Tj
2.3924 0 Td
(agent)Tj
2.296 0 Td
(is)Tj
0.8107 0 Td
(a)Tj
0.635 0 Td
(drug)Tj
2.0353 0 Td
(that)Tj
1.7007 0 Td
(is)Tj
0.8107 0 Td
(able)Tj
1.7575 0 Td
(to)Tj
0.9865 0 Td
(recognize)Tj
3.8891 0 Td
(one)Tj
-36.1018 -1.3039 Td
(or)Tj
1.0601 0 Td
(more)Tj
2.262 0 Td
(specific)Tj
3.0388 0 Td
(molecules)Tj
4.0308 0 Td
(expressed)Tj
3.9231 0 Td
(by)Tj
1.1452 0 Td
(tumor)Tj
2.6476 0 Td
(cells,)Tj
2.0295 0 Td
(immune)Tj
3.515 0 Td
(cells)Tj
1.8255 0 Td
(or,)Tj
1.2642 0 Td
(more)Tj
2.2677 0 Td
(generally,)Tj
3.8665 0 Td
(by)Tj
1.1452 0 Td
(tumor)Tj
-34.0212 -1.2983 Td
(microenvironment)Tj
7.5117 0 Td
(in)Tj
0.9978 0 Td
(cancer)Tj
2.7326 0 Td
(patients.)Tj
3.4242 0 Td
(The)Tj
1.7235 0 Td
(identification)Tj
5.3177 0 Td
(procedure)Tj
4.1443 0 Td
(has)Tj
1.4853 0 Td
(been)Tj
2.0466 0 Td
(rather)Tj
2.5342 0 Td
(complex)Tj
3.4866 0 Td
(-it)Tj
-35.4045 -1.2982 Td
(mirrors)Tj
3.1521 0 Td
(the)Tj
1.4173 0 Td
(complexity)Tj
4.4503 0 Td
(of)Tj
0.9751 0 Td
(the)Tj
1.4117 0 Td
(faced)Tj
2.2223 0 Td
(problem-)Tj
3.8098 0 Td
(and)Tj
1.6781 0 Td
(represents)Tj
4.1272 0 Td
(a)Tj
0.635 0 Td
(relevant)Tj
3.2711 0 Td
(step)Tj
1.7405 0 Td
(of)Tj
0.9751 0 Td
(the)Tj
1.4173 0 Td
(research.)Tj
-0.004 Tc
-30.0867 -1.3039 Td
(Furthermore,)Tj
5.6182 0 Td
(we)Tj
1.3266 0 Td
(have)Tj
2.0579 0 Td
(employed)Tj
4.1443 0 Td
(a)Tj
0.6519 0 Td
(method)Tj
3.3222 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(Voronoi)Tj
3.6226 0 Td
(tessellation)Tj
4.6375 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(],)Tj
2.0749 0 Td
(which)Tj
2.6533 0 Td
(repre-)Tj
-35.053 -1.2983 Td
(sents)Tj
2.211 0 Td
(a)Tj
0.6519 0 Td
(potential)Tj
3.7644 0 Td
(visualization)Tj
5.2441 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(subgroups)Tj
4.3653 0 Td
(identified)Tj
4.0592 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.474 0 Td
(cluster)Tj
2.8687 0 Td
(analysis.)Tj
3.5546 0 Td
(Voronoi)Tj
3.6227 0 Td
(dia-)Tj
-35.4782 -1.2983 Td
(gram)Tj
2.3073 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(kind)Tj
2.0636 0 Td
(of)Tj
1.0148 0 Td
(decomposition)Tj
6.1908 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(given)Tj
2.3754 0 Td
(metric)Tj
2.8233 0 Td
(space)Tj
2.381 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(distance)Tj
3.5036 0 Td
(\(which)Tj
2.9933 0 Td
(is)Tj
-34.0438 -1.3039 Td
(Euclidean)Tj
4.1839 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(original)Tj
3.3278 0 Td
(formulation)Tj
5.0343 0 Td
(of)Tj
1.0148 0 Td
(Voronoi\))Tj
3.9628 0 Td
(to)Tj
1.0262 0 Td
(specified)Tj
3.719 0 Td
(sites)Tj
1.9275 0 Td
(called)Tj
2.5229 0 Td
(centroids)Tj
3.9514 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(].)Tj
2.075 0 Td
(Par-)Tj
-35.2514 -1.2982 Td
(ticularly,)Tj
3.7133 0 Td
(each)Tj
2.0296 0 Td
(centroid)Tj
3.5886 0 Td
(recognizes)Tj
4.4221 0 Td
(data)Tj
1.9105 0 Td
(that)Tj
1.7801 0 Td
(are)Tj
1.4514 0 Td
(nearer)Tj
2.7893 0 Td
(to)Tj
1.0261 0 Td
(it)Tj
0.788 0 Td
(than)Tj
2.0239 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.474 0 Td
(other)Tj
2.3471 0 Td
(centroids)Tj
3.9458 0 Td
(in)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 107.1496 23.6976 re
W* n
q
107.0929 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 421.6818 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Toxicity)Tj
3.5575 0 Td
(and)Tj
1.8567 0 Td
(cost)Tj
2.0268 0 Td
(of)Tj
1.0417 0 Td
(oncolog)Tj
3.4299 0 Td
(ical)Tj
1.6867 0 Td
(target)Tj
2.7354 0 Td
(agents)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01836)Tj
4.089 0 Td
(39)Tj
0 g
2.0906 0 Td
(August)Tj
3.2882 0 Td
(22,)Tj
1.5874 0 Td
(2017)Tj
34.0302 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
28 0 obj
<>stream
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
endstream
endobj
33 0 obj
<>stream
endstream
endobj
34 0 obj
<>stream
endstream
endobj
35 0 obj
<>stream
endstream
endobj
36 0 obj
<>stream
endstream
endobj
37 0 obj
<>stream
endstream
endobj
38 0 obj
<>stream
endstream
endobj
39 0 obj
<>stream
endstream
endobj
40 0 obj
<>stream
BT
66.402 0 Td
(17)Tj
ET
Q
endstream
endobj
41 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 8 0 R/Annots 43 0 R/Contents 44 0 R/TrimBox[0 0 612 792]>>
endobj
43 0 obj
[45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R]
endobj
45 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref022)>>
endobj
46 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref025)>>
endobj
47 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref022)>>
endobj
48 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref023)>>
endobj
49 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.ref026)>>
endobj
50 0 obj
<>/Border[0 0 0]/Dest(Rpone.0183639.s001)>>
endobj
51 0 obj
<>/Border[0 0 0]/A 52 0 R>>
endobj
52 0 obj
<>
endobj
44 0 obj
[53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R 59 0 R 60 0 R]
endobj
53 0 obj
<>stream
q
0.83 0.64 0.02 0 k
279.2126 628.3276 m
288.737 628.3276 l
h
f*
293.8961 628.3276 m
303.4205 628.3276 l
h
f*
385.4551 628.3276 m
394.9795 628.3276 l
h
f*
224.0504 589.3228 m
233.5748 589.3228 l
h
f*
308.3528 328.9323 m
317.8772 328.9323 l
h
f*
326.8913 328.9323 m
353.2535 328.9323 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(accord)Tj
2.9083 0 Td
(to)Tj
1.0204 0 Td
(the)Tj
1.4741 0 Td
(given)Tj
2.3754 0 Td
(distance.)Tj
3.7303 0 Td
(By)Tj
1.2529 0 Td
(applying)Tj
3.6737 0 Td
(this)Tj
1.6725 0 Td
(technique,)Tj
4.3936 0 Td
(we)Tj
1.3266 0 Td
(are)Tj
1.4514 0 Td
(able)Tj
1.8255 0 Td
(to)Tj
1.0261 0 Td
(explore)Tj
3.1748 0 Td
(the)Tj
1.4683 0 Td
(way)Tj
1.7972 0 Td
(in)Tj
-34.5711 -1.3039 Td
(which)Tj
2.6475 0 Td
(clusters)Tj
3.2315 0 Td
(of)Tj
1.0148 0 Td
(toxicity)Tj
3.2031 0 Td
(and)Tj
1.7291 0 Td
(costs)Tj
2.1713 0 Td
(overlap,)Tj
3.4016 0 Td
(hence)Tj
2.5682 0 Td
(giving)Tj
2.6872 0 Td
(information)Tj
5.074 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(relationship)Tj
-30.4722 -1.2982 Td
(between)Tj
3.5262 0 Td
(drug)Tj
2.1147 0 Td
(toxicity)Tj
3.1974 0 Td
(and)Tj
1.7348 0 Td
(related)Tj
2.9424 0 Td
(cost.)Tj
-12.3193 -1.2983 Td
(As)Tj
1.2699 0 Td
(we)Tj
1.3266 0 Td
(will)Tj
1.6611 0 Td
(see)Tj
1.4286 0 Td
(below,)Tj
2.812 0 Td
(to)Tj
1.0261 0 Td
(gain)Tj
1.9332 0 Td
(more)Tj
2.3414 0 Td
(insights)Tj
3.3165 0 Td
(we)Tj
1.3267 0 Td
(depart)Tj
2.7949 0 Td
(from)Tj
2.2053 0 Td
(the)Tj
1.4684 0 Td
(original)Tj
3.3278 0 Td
(formulation)Tj
5.0343 0 Td
(of)Tj
1.0148 0 Td
(Vor-)Tj
-35.4838 -1.2983 Td
(onoi)Tj
2.0466 0 Td
(and)Tj
1.7291 0 Td
(consider)Tj
3.651 0 Td
(also)Tj
1.7688 0 Td
(minimum)Tj
4.2916 0 Td
(and)Tj
1.7291 0 Td
(maximum)Tj
4.371 0 Td
(distances.)Tj
-18.391 -1.3039 Td
(Cluster)Tj
3.1124 0 Td
(analysis,)Tj
3.5546 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6519 0 Td
(specific)Tj
3.1918 0 Td
(Voronoi)Tj
3.6227 0 Td
(diagrams)Tj
3.9004 0 Td
(approach,)Tj
4.1783 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(recently)Tj
3.4129 0 Td
(applied)Tj
3.1521 0 Td
(in)Tj
-35.6312 -1.2982 Td
(the)Tj
1.4683 0 Td
(economic)Tj
4.1385 0 Td
(field)Tj
1.9729 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
(].)Tj
3.5433 0 Td
(In)Tj
1.1112 0 Td
(2009,)Tj
2.3471 0 Td
(Liu)Tj
1.5534 0 Td
(et)Tj
0.941 0 Td
(al.)Tj
1.1282 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(])Tj
1.8482 0 Td
(explored)Tj
3.702 0 Td
(the)Tj
1.474 0 Td
(distribution)Tj
4.9663 0 Td
(of)Tj
1.0148 0 Td
(rural)Tj
2.1713 0 Td
(assess-)Tj
-33.3805 -1.2983 Td
(ment)Tj
2.3073 0 Td
(using)Tj
2.3925 0 Td
(this)Tj
1.6724 0 Td
(technique.)Tj
4.3937 0 Td
(They)Tj
2.2337 0 Td
(showed)Tj
3.2541 0 Td
(that)Tj
1.7802 0 Td
(the)Tj
1.4683 0 Td
(distance)Tj
3.5036 0 Td
(from)Tj
2.2053 0 Td
(highways)Tj
3.9402 0 Td
(and)Tj
1.7291 0 Td
(rivers)Tj
2.4718 0 Td
(were)Tj
2.1203 0 Td
(the)Tj
-35.4725 -1.3039 Td
(two)Tj
1.7064 0 Td
(factors)Tj
2.9027 0 Td
(that)Tj
1.7801 0 Td
(majorly)Tj
3.3108 0 Td
(influenced)Tj
4.4447 0 Td
(the)Tj
1.4684 0 Td
(distribution)Tj
4.9662 0 Td
(of)Tj
1.0148 0 Td
(rural)Tj
2.1714 0 Td
(settlements.)Tj
4.9492 0 Td
(More)Tj
2.4151 0 Td
(recently,)Tj
3.634 0 Td
(Vaz)Tj
-34.7638 -1.2983 Td
(et)Tj
0.941 0 Td
(al.)Tj
1.1226 0 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(])Tj
1.8538 0 Td
(reported)Tj
3.6623 0 Td
(a)Tj
0.652 0 Td
(significant)Tj
4.388 0 Td
(difference)Tj
4.2066 0 Td
(in)Tj
1.0318 0 Td
(term)Tj
2.1373 0 Td
(of)Tj
1.0148 0 Td
(regional)Tj
3.4809 0 Td
(innovation)Tj
4.5978 0 Td
(patterns)Tj
3.4753 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(conse-)Tj
-34.2309 -1.2983 Td
(quence)Tj
3.0727 0 Td
(of)Tj
1.0148 0 Td
(istitutional)Tj
4.5411 0 Td
(innovation)Tj
4.5977 0 Td
(profiles.)Tj
-12.0301 -1.3039 Td
(As)Tj
1.2699 0 Td
(already)Tj
3.1067 0 Td
(mentioned)Tj
4.5865 0 Td
(above,)Tj
2.7722 0 Td
(we)Tj
1.3266 0 Td
(here)Tj
1.9673 0 Td
(investigate,)Tj
4.6828 0 Td
(through)Tj
3.4469 0 Td
(a)Tj
0.6576 0 Td
(cluster)Tj
2.8686 0 Td
(analysis)Tj
3.3279 0 Td
(procedure,)Tj
-31.2092 -1.2982 Td
(whether)Tj
3.4752 0 Td
(there)Tj
2.262 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(correlation)Tj
4.6204 0 Td
(between)Tj
3.5263 0 Td
(the)Tj
1.4683 0 Td
(cost)Tj
1.8142 0 Td
(of)Tj
1.0148 0 Td
(molecularly)Tj
4.9209 0 Td
(targeted)Tj
3.4583 0 Td
(and)Tj
1.7291 0 Td
(immnotherapy)Tj
-29.7919 -1.2983 Td
(agents)Tj
2.7495 0 Td
(and)Tj
1.7292 0 Td
(their)Tj
2.1089 0 Td
(toxicity)Tj
3.2032 0 Td
(in)Tj
1.0318 0 Td
(terms)Tj
2.4944 0 Td
(of)Tj
1.0148 0 Td
(SAE)Tj
1.9503 0 Td
(and)Tj
1.7291 0 Td
(D)Tj
0.9581 0 Td
(rates.)Tj
-17.7731 -1.3039 Td
(To)Tj
1.3379 0 Td
(the)Tj
1.474 0 Td
(best)Tj
1.8085 0 Td
(of)Tj
1.0148 0 Td
(our)Tj
1.6271 0 Td
(knowledge,)Tj
4.7678 0 Td
(this)Tj
1.6725 0 Td
(is)Tj
0.8503 0 Td
(the)Tj
1.4684 0 Td
(first)Tj
1.8028 0 Td
(paper)Tj
2.4831 0 Td
(dealing)Tj
3.1351 0 Td
(with)Tj
1.9956 0 Td
(toxicity)Tj
3.2031 0 Td
(and)Tj
1.7292 0 Td
(cost)Tj
1.8085 0 Td
(of)Tj
1.0148 0 Td
(target)Tj
-34.3897 -1.2983 Td
(agents)Tj
2.7495 0 Td
(in)Tj
1.0375 0 Td
(oncology)Tj
3.8778 0 Td
(through)Tj
3.4469 0 Td
(a)Tj
0.652 0 Td
(cluster)Tj
2.8686 0 Td
(analysis.)Tj
3.5546 0 Td
(More)Tj
2.4151 0 Td
(than)Tj
2.0296 0 Td
(this,)Tj
1.8992 0 Td
(the)Tj
1.4684 0 Td
(construction)Tj
5.3007 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(dataset)Tj
-33.783 -1.2982 Td
(on)Tj
1.2755 0 Td
(the)Tj
1.4684 0 Td
(basis)Tj
2.1486 0 Td
(of)Tj
1.0148 0 Td
(an)Tj
1.2019 0 Td
(exhaustive)Tj
4.405 0 Td
(literature)Tj
3.8834 0 Td
(review)Tj
2.8403 0 Td
(is)Tj
0.8504 0 Td
(also)Tj
1.7688 0 Td
(a)Tj
0.652 0 Td
(novelty)Tj
3.1521 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(oncological)Tj
4.7962 0 Td
(studies.)Tj
-30.767 -1.2983 Td
(The)Tj
1.7858 0 Td
(rest)Tj
1.6724 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(paper)Tj
2.4832 0 Td
(is)Tj
0.8504 0 Td
(organized)Tj
4.1782 0 Td
(as)Tj
1.0148 0 Td
(follows.)Tj
3.2825 0 Td
(Section)Tj
3.1634 0 Td
(2)Tj
0.6974 0 Td
(collects)Tj
3.1464 0 Td
(the)Tj
1.474 0 Td
(results)Tj
2.8063 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(analysis,)Tj
-32.7172 -1.3039 Td
(while)Tj
2.3697 0 Td
(Section)Tj
3.1634 0 Td
(3)Tj
0.6917 0 Td
(provides)Tj
3.651 0 Td
(a)Tj
0.652 0 Td
(discussion)Tj
4.371 0 Td
(of)Tj
1.0148 0 Td
(them.)Tj
2.5171 0 Td
(In)Tj
1.1112 0 Td
(Section)Tj
3.1634 0 Td
(4)Tj
0.6917 0 Td
(we)Tj
1.3322 0 Td
(present)Tj
3.1635 0 Td
(how)Tj
1.9389 0 Td
(the)Tj
1.4683 0 Td
(used)Tj
2.058 0 Td
(dataset)Tj
-33.3579 -1.2983 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(constructed)Tj
4.9322 0 Td
(and)Tj
1.7292 0 Td
(illustrate)Tj
3.6963 0 Td
(its)Tj
1.1452 0 Td
(main)Tj
2.2904 0 Td
(statistical)Tj
3.9061 0 Td
(properties.)Tj
4.5014 0 Td
(Furthermore,)Tj
5.6182 0 Td
(Section)Tj
3.1635 0 Td
(4)Tj
0.6973 0 Td
(con-)Tj
-35.3421 -1.2983 Td
(tains)Tj
2.1259 0 Td
(also)Tj
1.7688 0 Td
(the)Tj
1.4684 0 Td
(description)Tj
4.7338 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(employed)Tj
4.1443 0 Td
(methodological)Tj
6.4176 0 Td
(tools,)Tj
2.364 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6576 0 Td
(detailed)Tj
3.3676 0 Td
(explanation)Tj
4.9096 0 Td
(of)Tj
-36.4363 -1.3039 Td
(the)Tj
1.4683 0 Td
(cluster)Tj
2.8743 0 Td
(analysis.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 403.9937 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Materials)Tj
4.5071 0 Td
(and)Tj
1.989 0 Td
(methods)Tj
/F0 1 Tf
-6.4961 -1.4976 Td
(Costruction)Tj
5.2205 0 Td
(of)Tj
1.0441 0 Td
(the)Tj
1.5968 0 Td
(dataset)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 369.0141 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(The)Tj
1.7801 0 Td
(construction)Tj
5.3008 0 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4741 0 Td
(dataset)Tj
2.9933 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1259 0 Td
(implemented)Tj
5.5332 0 Td
(through)Tj
3.4469 0 Td
(a)Tj
0.652 0 Td
(critical)Tj
2.9537 0 Td
(analysis)Tj
3.3222 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(wide)Tj
2.1203 0 Td
(set)Tj
-35.9317 -1.3039 Td
(of)Tj
1.0147 0 Td
(clinical)Tj
3.0728 0 Td
(studies.)Tj
-2.8913 -1.2982 Td
(The)Tj
1.7858 0 Td
(selection)Tj
3.719 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(relevant)Tj
3.4186 0 Td
(researchs)Tj
3.9175 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.126 0 Td
(carried)Tj
3.0387 0 Td
(out)Tj
1.5534 0 Td
(according)Tj
4.1839 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4683 0 Td
(instructions)Tj
-31.4586 -1.2983 Td
(contained)Tj
4.1952 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(PRISMA)Tj
3.7927 0 Td
([)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(])Tj
1.8539 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
1.508 0 Td
(File)Tj
0 g
(\).)Tj
2.2507 0 Td
(The)Tj
1.7858 0 Td
(scientific)Tj
3.7871 0 Td
(literature)Tj
3.8778 0 Td
(of)Tj
1.0148 0 Td
(interest)Tj
3.2144 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1203 0 Td
(identified)Tj
-33.4486 -1.2983 Td
(from)Tj
2.2053 0 Td
(keywords)Tj
4.0478 0 Td
(selections)Tj
4.0762 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(PubMed)Tj
3.6566 0 Td
(database,)Tj
3.8665 0 Td
(in)Tj
1.0374 0 Td
(a)Tj
0.652 0 Td
(period)Tj
2.8346 0 Td
(ranging)Tj
3.3222 0 Td
(from)Tj
2.2053 0 Td
(1965)Tj
2.1203 0 Td
(to)Tj
1.0262 0 Td
(2016.)Tj
-33.7944 -1.3039 Td
(Specifically,)Tj
4.9095 0 Td
(the)Tj
1.4684 0 Td
(research)Tj
3.5603 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(conducted)Tj
4.4277 0 Td
(by)Tj
1.1849 0 Td
(combining)Tj
4.5694 0 Td
(the)Tj
1.474 0 Td
(words)Tj
2.6702 0 Td
("cancer",)Tj
3.7077 0 Td
("neoplasm",)Tj
-31.6344 -1.2982 Td
("solid)Tj
2.4491 0 Td
(tumor")Tj
3.0614 0 Td
(and)Tj
1.7291 0 Td
("clinical)Tj
3.3959 0 Td
(trial")Tj
2.1543 0 Td
(with)Tj
2.0012 0 Td
(the)Tj
1.4684 0 Td
(name)Tj
2.4434 0 Td
(of)Tj
1.0148 0 Td
(each)Tj
2.0296 0 Td
(target)Tj
2.5115 0 Td
(agent.)Tj
-23.0625 -1.2983 Td
(As)Tj
1.2585 0 Td
(a)Tj
0.6463 0 Td
(second)Tj
3.0047 0 Td
(step,)Tj
2.041 0 Td
(we)Tj
1.3209 0 Td
(have)Tj
2.0523 0 Td
(identified)Tj
4.0478 0 Td
(the)Tj
1.4627 0 Td
(papers)Tj
2.8403 0 Td
(dealing)Tj
3.1238 0 Td
(with)Tj
1.9899 0 Td
(human)Tj
3.067 0 Td
(studies)Tj
2.9821 0 Td
(and)Tj
1.7234 0 Td
(randomized)Tj
-32.7569 -1.3039 Td
(trials)Tj
2.194 0 Td
(published)Tj
4.1272 0 Td
(in)Tj
1.0374 0 Td
(English)Tj
3.2032 0 Td
(and)Tj
1.7291 0 Td
(meeting)Tj
3.4696 0 Td
(the)Tj
1.4683 0 Td
(following)Tj
3.9798 0 Td
(criteria:)Tj
3.2995 0 Td
(1\))Tj
1.0375 0 Td
(phase)Tj
2.4831 0 Td
(III)Tj
1.2416 0 Td
(studies)Tj
2.982 0 Td
(conducted)Tj
4.4277 0 Td
(in)Tj
-36.68 -1.2983 Td
(patients)Tj
3.3675 0 Td
(with)Tj
1.9956 0 Td
(cancer;)Tj
3.0727 0 Td
(2\))Tj
1.0318 0 Td
(random)Tj
3.4299 0 Td
(assignment)Tj
4.7452 0 Td
(of)Tj
1.0148 0 Td
(participants)Tj
4.9606 0 Td
(to)Tj
1.0261 0 Td
(treatment)Tj
4.1329 0 Td
(with)Tj
2.0012 0 Td
(a)Tj
0.652 0 Td
(target)Tj
2.5115 0 Td
(therapy)Tj
-33.9418 -1.2983 Td
(or)Tj
1.0941 0 Td
(a)Tj
0.6576 0 Td
(control)Tj
3.1238 0 Td
(\(standard)Tj
4.0592 0 Td
(of)Tj
1.0148 0 Td
(care,)Tj
2.0976 0 Td
(placebo)Tj
3.2768 0 Td
(or)Tj
1.0999 0 Td
(best)Tj
1.8085 0 Td
(supportive)Tj
4.4673 0 Td
(care\).)Tj
2.4378 0 Td
(In)Tj
1.1055 0 Td
(case)Tj
1.8652 0 Td
(of)Tj
1.0148 0 Td
(several)Tj
2.931 0 Td
(publications)Tj
-32.0539 -1.3039 Td
(related)Tj
2.9423 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(same)Tj
2.262 0 Td
(experiment,)Tj
5.0003 0 Td
(only)Tj
1.9786 0 Td
(the)Tj
1.4683 0 Td
(most)Tj
2.2053 0 Td
(recent)Tj
2.7099 0 Td
(one)Tj
1.7008 0 Td
(or)Tj
1.0942 0 Td
(the)Tj
1.474 0 Td
(most)Tj
2.2053 0 Td
(complete)Tj
3.8778 0 Td
(referring)Tj
3.7474 0 Td
(to)Tj
-35.1607 -1.2982 Td
(included)Tj
3.7133 0 Td
(trial)Tj
1.8369 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(considered.)Tj
4.8245 0 Td
(Phase)Tj
2.5285 0 Td
(I)Tj
0.5613 0 Td
(and)Tj
1.7291 0 Td
(phase)Tj
2.4831 0 Td
(II)Tj
0.9014 0 Td
(trials)Tj
2.194 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.126 0 Td
(excluded)Tj
3.7813 0 Td
(because)Tj
3.3222 0 Td
(of)Tj
-35.206 -1.2983 Td
(their)Tj
2.1089 0 Td
(variability)Tj
4.2179 0 Td
(and)Tj
1.7292 0 Td
(the)Tj
1.474 0 Td
(lack)Tj
1.8198 0 Td
(of)Tj
1.0148 0 Td
(sufficient)Tj
3.9118 0 Td
(controls.)Tj
-15.0802 -1.3039 Td
(For)Tj
-0.01 Tc
1.6214 0 Td
(each)Tj
1.9955 0 Td
(of)Tj
0.9978 0 Td
(the)Tj
1.4457 0 Td
(obtained)Tj
3.6737 0 Td
(papers)Tj
2.8006 0 Td
(we)Tj
1.3096 0 Td
(have)Tj
2.0296 0 Td
(reported)Tj
3.6056 0 Td
(the)Tj
1.44 0 Td
(scientific)Tj
3.7247 0 Td
(study,)Tj
2.5682 0 Td
(the)Tj
1.4457 0 Td
(name)Tj
2.4151 0 Td
(of)Tj
0.9921 0 Td
(all)Tj
1.1225 0 Td
(authors,)Tj
-34.384 -1.2983 Td
(the)Tj
1.4513 0 Td
(name)Tj
2.4208 0 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4513 0 Td
(journal,)Tj
3.2882 0 Td
(the)Tj
1.4513 0 Td
(reference)Tj
3.8665 0 Td
(year,)Tj
2.0976 0 Td
(the)Tj
1.4513 0 Td
(number)Tj
3.3789 0 Td
(of)Tj
1.0035 0 Td
(the)Tj
1.4513 0 Td
(volume)Tj
3.1634 0 Td
(and)Tj
1.7121 0 Td
(the)Tj
1.4514 0 Td
(reference)Tj
3.8664 0 Td
(pages.)Tj
-0.004 Tc
-33.3125 -1.2982 Td
(The)Tj
1.7858 0 Td
(resulting)Tj
3.7303 0 Td
(list)Tj
1.389 0 Td
(of)Tj
1.0148 0 Td
(studies)Tj
2.9877 0 Td
(on)Tj
1.2756 0 Td
(target)Tj
2.5115 0 Td
(agents)Tj
2.7496 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.126 0 Td
(explored)Tj
3.6963 0 Td
(to)Tj
1.0262 0 Td
(assess)Tj
2.5228 0 Td
(the)Tj
1.4683 0 Td
(variables)Tj
3.719 0 Td
(of)Tj
-34.7411 -1.2983 Td
(interest)Tj
3.2087 0 Td
(related)Tj
2.9481 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4683 0 Td
(specific)Tj
3.1918 0 Td
(agent,)Tj
2.6136 0 Td
(i.e.:)Tj
1.5873 0 Td
(number)Tj
3.4186 0 Td
(of)Tj
1.0148 0 Td
(patients)Tj
3.3675 0 Td
(treated)Tj
2.9934 0 Td
(with)Tj
2.0013 0 Td
(target)Tj
2.5058 0 Td
(agents)Tj
2.7552 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
-35.1323 -1.3039 Td
(clinical)Tj
3.0727 0 Td
(studies,)Tj
3.2145 0 Td
(PFS)Tj
1.7801 0 Td
(\(defined)Tj
3.566 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(time)Tj
2.0239 0 Td
(from)Tj
2.2053 0 Td
(the)Tj
1.474 0 Td
(start)Tj
1.9786 0 Td
(of)Tj
1.0148 0 Td
(therapy)Tj
3.2485 0 Td
(to)Tj
1.0261 0 Td
(disease)Tj
3.0161 0 Td
(progression)Tj
4.9209 0 Td
(or)Tj
-35.0303 -1.2983 Td
(death\),)Tj
2.9933 0 Td
(rate)Tj
1.7518 0 Td
(of)Tj
1.0148 0 Td
(all-grade)Tj
3.7134 0 Td
(AE)Tj
1.474 0 Td
(and)Tj
1.7348 0 Td
(SAE)Tj
1.9445 0 Td
(\(which)Tj
2.9934 0 Td
(leads)Tj
2.211 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(necessity)Tj
3.7814 0 Td
(of)Tj
1.0148 0 Td
(medical)Tj
3.3618 0 Td
(assistence,)Tj
4.3484 0 Td
(hospi-)Tj
-34.8319 -1.2983 Td
(talization)Tj
3.9344 0 Td
(or)Tj
1.0942 0 Td
(drug)Tj
2.1146 0 Td
(interruption\))Tj
5.5049 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.474 0 Td
(D)Tj
0.9524 0 Td
(rate)Tj
1.7462 0 Td
(due)Tj
1.7007 0 Td
(to)Tj
1.0262 0 Td
(drug)Tj
2.1146 0 Td
(toxicity.)Tj
-22.1951 -1.3039 Td
(For)Tj
1.627 0 Td
(the)Tj
1.4684 0 Td
(present)Tj
3.1691 0 Td
(research,)Tj
3.7757 0 Td
(we)Tj
1.3323 0 Td
(consider)Tj
3.6453 0 Td
(as)Tj
1.0148 0 Td
(variables)Tj
3.719 0 Td
(the)Tj
1.4741 0 Td
(rate)Tj
1.7461 0 Td
(of)Tj
1.0148 0 Td
(SAE)Tj
1.9502 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(D)Tj
0.9581 0 Td
(rate,)Tj
1.9729 0 Td
(leaving)Tj
3.0557 0 Td
(the)Tj
-36.3172 -1.2982 Td
(other)Tj
2.347 0 Td
(ones)Tj
2.058 0 Td
(for)Tj
1.3889 0 Td
(future)Tj
2.6532 0 Td
(studies.)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 107.1496 23.6976 re
W* n
q
107.0929 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 421.6818 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Toxicity)Tj
3.5575 0 Td
(and)Tj
1.8567 0 Td
(cost)Tj
2.0268 0 Td
(of)Tj
1.0417 0 Td
(oncolog)Tj
3.4299 0 Td
(ical)Tj
1.6867 0 Td
(target)Tj
2.7354 0 Td
(agents)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01836)Tj
4.089 0 Td
(39)Tj
0 g
2.0906 0 Td
(August)Tj
3.2882 0 Td
(22,)Tj
1.5874 0 Td
(2017)Tj
34.0302 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
54 0 obj
<>stream
endstream
endobj
55 0 obj
<>stream
endstream
endobj
56 0 obj
<>stream
endstream
endobj
57 0 obj
<>stream
endstream
endobj
58 0 obj
<>stream
endstream
endobj
59 0 obj
<>stream
endstream
endobj
60 0 obj
<>stream
BT
66.402 0 Td
(17)Tj
ET
Q
endstream
endobj
61 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 8 0 R/Annots 67 0 R/Contents 68 0 R/TrimBox[0 0 612 792]>>
endobj
63 0 obj
<>
endobj
69 0 obj
<>
endobj
70 0 obj
<>stream
%!PS-AdobeFont-1.0
11 dict begin
/FontName /TeX_CM_Roman def
/FontType 1 def
/FontBBox {-31 -250 1000 750} readonly def
/FontMatrix [0.001 0 0 0.001 0 0] readonly def
/PaintType 0 def
/FontInfo 8 dict dup begin
/FullName (TeX_CM_Roman) readonly def
/BaseFontName (TeX_CM_Roman) def
end def
/Encoding 256 array
0 1 255 {1 index exch /.notdef put} for
dup 0 /C0 put
dup 1 /C1 put
dup 2 /C2 put
dup 3 /C3 put
dup 4 /C4 put
dup 5 /C5 put
dup 6 /C6 put
dup 7 /C7 put
dup 8 /C8 put
dup 9 /C9 put
dup 10 /C10 put
dup 11 /C11 put
dup 12 /C12 put
dup 13 /C13 put
dup 14 /C14 put
dup 15 /C15 put
dup 16 /C16 put
dup 17 /C17 put
dup 18 /C18 put
dup 19 /C19 put
dup 20 /C20 put
dup 21 /C21 put
dup 22 /C22 put
dup 23 /C23 put
dup 24 /C24 put
dup 25 /C25 put
dup 26 /C26 put
dup 27 /C27 put
dup 28 /C28 put
dup 29 /C29 put
dup 30 /C30 put
dup 31 /C31 put
dup 32 /space put
dup 33 /exclam put
dup 34 /quotedbl put
dup 35 /numbersign put
dup 36 /dollar put
dup 37 /percent put
dup 38 /ampersand put
dup 39 /quoteright put
dup 40 /parenleft put
dup 41 /parenright put
dup 42 /asterisk put
dup 43 /plus put
dup 44 /comma put
dup 45 /hyphen put
dup 46 /period put
dup 47 /slash put
dup 48 /zero put
dup 49 /one put
dup 50 /two put
dup 51 /three put
dup 52 /four put
dup 53 /five put
dup 54 /six put
dup 55 /seven put
dup 56 /eight put
dup 57 /nine put
dup 58 /colon put
dup 59 /semicolon put
dup 60 /less put
dup 61 /equal put
dup 62 /greater put
dup 63 /question put
dup 64 /at put
dup 65 /A put
dup 66 /B put
dup 67 /C put
dup 68 /D put
dup 69 /E put
dup 70 /F put
dup 71 /G put
dup 72 /H put
dup 73 /I put
dup 74 /J put
dup 75 /K put
dup 76 /L put
dup 77 /M put
dup 78 /N put
dup 79 /O put
dup 80 /P put
dup 81 /Q put
dup 82 /R put
dup 83 /S put
dup 84 /T put
dup 85 /U put
dup 86 /V put
dup 87 /W put
dup 88 /X put
dup 89 /Y put
dup 90 /Z put
dup 91 /bracketleft put
dup 92 /backslash put
dup 93 /bracketright put
dup 94 /asciicircum put
dup 95 /underscore put
dup 96 /quoteleft put
dup 97 /a put
dup 98 /b put
dup 99 /c put
dup 100 /d put
dup 101 /e put
dup 102 /f put
dup 103 /g put
dup 104 /h put
dup 105 /i put
dup 106 /j put
dup 107 /k put
dup 108 /l put
dup 109 /m put
dup 110 /n put
dup 111 /o put
dup 112 /p put
dup 113 /q put
dup 114 /r put
dup 115 /s put
dup 116 /t put
dup 117 /u put
dup 118 /v put
dup 119 /w put
dup 120 /x put
dup 121 /y put
dup 122 /z put
dup 123 /braceleft put
dup 124 /bar put
dup 125 /braceright put
dup 126 /asciitilde put
dup 127 /Euro put
readonly def
currentdict end
currentfile eexec
M#1H5 J6o\&rtS(#v\0\V7Fe༙OYx5-cY9^%Y6
(efIOldN"wȰ;)UƽoFg/rvV$JS8_oc@
o9-eGJp}[Do]mN=4*{ܯq=eU^t6¤.vA2*Sr 2@Y0}S/8W}efFz~"7Mԗ3T3#mAE=90}c:o|y$)|DKf{(!✱դs'Xt{r6\C~-x{jFҘ{@]##')\}7l"ۂ8c.)a0KcyZ$FX(uØ!{uh\[l^d*BֿAJyPOM lJvNab?$h:`/A[ 88hxtXX*UT<NoR^@z
!cef WE(3ZmC:A~Y&w$ř/LGjq6Sπ4E0rrdyrx˫3JLqT|heT[?bqv\6Kw0ֻ#[[#Fo碜m w#ojsnlϴ=9 Żԕ)~\]G˧Ž9#iiՋToI.9[ڔl6l_vtK"JfKPč+:
Α/ (kw}
>qoF6EQO8Ql68ůĊɻ֕GNKEvw*70Uz7+*t8w͌`уg;5unV#/-VPoWHY+H%5̶bGPgsPU
v
"h$9;Ap52@\_A-0@i:0&"MW\45@27wRItgtEa5 ew#oH}TȒ)HEY$@W`rTmŽ^xlIC' U:* 3?RCG
hk~sA9+cUɅ;eoYyv@54oR
UeYPΚmu[*՛4z3vIk9UBřR29kӧf4ی4o0H?ǚ<._VhZu*`h>S
ao҄Ã(Kh',9s&/b$fGX==s2:=x?B<Ӂ:ͪbJ*EgDEg|s8, 1 4f&raBڶ]٠}$*U"*/y"7.VgS+'Q6h"3$\އ7U9چۯj1}21WH;=|{pb=x@OѢ^[ngoDU'suIҢ!+VCAb2BsSm
x\=Q,pt響m!.;jX2_f;_$䦐>{ןŌR"=@M
k9٦LnQkջy{yg+_CJ;DU.2qKf ]cj[6$i/@f ^$JnY:4*itKD"_U5Zay";4\.a`a=Bhlru M:%_8Rx=mo9ިӍj&q&dWf?K
$r\;7oU'c{apDT=Zţ!.% c/=3tg|}AGd`#oe )hZ#Č4vQnTERz*uhc}(<T~?ԀlifF!W_Qo0>Tc?gߝv|K{&h{Qza
x
2)3jd@"wSt@![*SZ4\z;,ܵ
❦u@HpΒRMroҜq{z
(`wN
PcT(Sݣ\.]ƿ}/xb)7!P3hQRwYBІd|ՔF ֺw"m%r8= (Ah&x|Fz&E{fup&rxyzNt[AqR9M9N#C1cc9w\GCUN!RaoB$e W-U7ޓweaBoֳD(c6֧droG2tʈmV):ƣDa)r8>HrVm" cu40q?$-@;o,ZUHL6$ {%c#lV_.MBa6[+U3D?rfgv,m,۠8?4}ݏşcVRy5NRP_\Wz囔Zf}&5}Hf
ڗrm@0|NL}B婭$=;Ӻ֚Dȷ;NXf9&SR85+&W]
(
ţ8q ZITrM|bd
s娶 u" ]'Q+>@2Yƭ_vh\goܡn<g$wn_` _u\J!!.5^ ϓ/q
-s#+GzKcggh҇*FAV4cOcBGcf)=Bh(CX\@"8O{J
vXgn8nڧML'D/)(tD~/wF+Ќ:/+=z
EE0\a47 =c]c9H5vEYu{[7_G7>;12ч%V3iw\i ejS}K 74E.bo(/@Q-}]8TIռqw=5ѤrXO96z 96$oXIHLg_FeBP$f`>(R6q]htif N}HjV*dMv^?;[:4HFAe@5$۬x"mS~_wOn['[]a5N1&/8yiw; Dm֣@2Ur>xHDAɵFO\[D(ki=|[2Bo)ʽɢ=ȐU;,Э(W]lC!\OV5, aeI+u