Advances in Cancer Treatment

がん治療のあゆみ
2017/第37回一般研究助成

37

公益財団法人 がん集学的治療研究財団

! # "
ðY

;

¿

¡

q

>P]"äiP/¸O×òü;ðYPÅhLAJðYOúh4FASAF!ãRQ"9aPû[òOB]½©`!2!B]L¬O">^OB]2P`´4Ps`Î4"õOA;
IõPUòÇ`Z\Ç[OôÂB]ò`A"WHJÔPºËPÈ&OÐ¼B]>
L`[LAJ4SB!
ãRPöNð°LAJ,Iª=[^SB!*IVQ"Fí6¬a#½©%JFMC ½©&PôíKB!
9aPò%"EPE&`öLAJ"9aP#O_]Fí6¬a#½©`ó[

A"

ôíAJ4SB!+IV9"ym½©!2KB!9aPû[òOB]½©%#î¾LAJôí
jN#½©&`ym8[}ûA"*ÚP&"!2²`Ù&=J4SB!,IQ"êÆÏÛKB!
ÆãR/9aû[ò½©ãRPÆð°PyLAJ"êÆÏÛ`ÜAJ7\SB!
ãRQ"*21)iP6^ý8["ym½©!2ð°`èA",1iKÒ´+",,1¹P}`÷<"ym½©:ÍuzKÀüO*ÚAF·"-2*¹OHAJ"?/-"/1)P!2`ÎHJS4\SA
F!t;Q"£=½©X~#`´Pi$nWßNAJ4SAF9"Ý±Q"#î¾LAJôíjN
#½©`7AJßNAJ4SB!H$MQ"#9jLN\5]'Pû[ò(OB]½©KB!OA">^OB]½©"FL6RõPwP`µÁB]FVP½©"õOA4
y"Å{éP»å"g$oxPÌU"±4"\9¥I@^]£=[½©"NMP½©P}WLAJ4SB!í6Jrõ8[P09OZ\"}AJZ4J4SB!Ý±Q.)¹;ÅP}9D4
J7\"ßN`Í6]L3O«>[½©pLNHJ4SB!í6Jrõ`YQþCxY"½©þ

Y"t|YLAJ4SAF9"}PÄ`=]FVO"|2,)i]8[Qöh­ø"½©Y8[P09W÷<v<]>LLASB!!2¹1Q"EPñP³à(®OØ}@^J7\"ãRkB^ýQ*.¹"
F4ñQ*2¹P!2`AJç\SAF!A8A"ÂâQ"*¹1)".¹P!2LNHJ4SB!
ÕÅ"ãR9ôíB]lsdbckLAJ">^SKãRKV5@^FöOwXKXOB]K¦#î¾j$e``ÒA"Ê;ymOjN#î¾'~ DB PÌU`ëAJ7\SB!DBð°Wym½©!ð°La"°"t|8[P?ìPWLôíAJ7\">^[ð°`0.B]FVOÃF]ã£n9u¶K3]>LQ`GSDa!"[OP DB L`ÒB]>LK"g<GP#î¾PÔá[s9È&B]LLWO"ÕÅPLòkO@[O¤B]>L9jL
N\SBPK"{DJ?ìï\SBZ574-A&=SB!
@J"g7d<ASAF'9aòP3YTL,0(Q"|2+1i]÷%õP½©2P~ÓKB!
}¹1.-¹PW8[À:@^F.¹K3\"4C^WkhlrmqPÝ7QP½©KB!½©pc9ÖfN(®ONHJ:J7\"3O«>[½©pLNHJ:J4SB!H$@¢W;8")b"w"KX""LFÞK"ñJOAAF½©eK¯,4·9c[^J4SB!æéQãR9*21)i

P6^ý8[èAF'ym½©!2ð°(Pv¨`Ê;ùSB]§üN~ÓÿKBPK"?ÑZ:"?ol_`ï^RÉ4KB!>^SKO",1iKÒ´+",,1¹P}`÷<"ym½©:ÍuzKÀüO*ÚAF·"-2*¹OHAJ"?/-"/1)P!2`ÎHJS4\SAF!ð°P>^SK
P!2õQF;Pg`JrB]khlp$f$LAJ@^J4SB!Õi]W0¸Z\+FOÆ}TASBPK"zHJ}Z<^RÉ4KB!

d^?"N]Yu~Zrvn?Ae¥k#¢O"bS=5|§1D8:bMO@?E5¨jH"?*H0>,57+D8:!D:"~')@n=A.8+"5¨
1"5smKjHD8:_Qe{0L]YT¤¡P

P@f`t

?A"x/G@.

©>VpKy8w4D9!£J:]YK}z9Iqvo@$"5}+:;1D8:io@"2@$@§KUo6LKN?b-I0Ll¦"_Q?[4<+3JBa+=9!c^>E
eC@5hR"5g"5ªKjHD9F,"X82.W+y8w4D9!
~(%(\(&

%

#

"

!

&

$

^Ø{¸[_i

n

¸[_È

Æ

x



¸hVpÄH8åª;¨6M<!
À§gÃF;D"÷¥bð3eÕFGS0T$tI;"*- IbäVlÌõ%Hs<T{VäÉ4M;@!bäËN²SJ-)'ÒE"ºDIbä£øIXY#Vë}QSºDI¸[_H¾Ü;"¹ÚdV;D/@A4M;@!?I¹ÚdEJ"´ÀÚdIL2HÚd3àRG/Q0ÚdÖÝVÊ
N@¼ÀÚdEÎV1u/;D1SM<!
?I¸fVë}E

;"|T'&+ÒHÂ*(j^Ø{¸[_iVk;M;@!¸[_

3¨Z2R^Ã=CwûV¡ÝHBD"°HÚdV/M;@!7I¸[_iwúJ"ß­yKÐí­Vô;"]PòïVvú;"â¿;D1SM<!
?If",

IbägÃV¤®À§ãF;DòiH¨ª;"¦ÓÉ4M;@!

¤®Vö9UTµ±æH1u/;M<!
ÇråFGT2O;UM>W3"'ÔIèÍHD{fV×Ù;D/@A4M<!O;×Ù3
ÛeÕE.B@©J"¤®IáqVzNT7FO8:/M<!
M@"{ûÞV×Ù9UTHJ$3W

lÌõ{Å¤®%Iã¤VÑ@Vív;DÉ5

Q01u/;M<!Å2RI¤®½mJ"jMEE,c+¶éa~5HGSM<!tIõ{HîóBD/TOIF¬;D1SM<3"èÅJ`ç«E<IE"acknowledgement VÜ;@ûÞ
Vo/@A57FJ"¢ñG\êVBD1SM<!
HGSM;@3"¤®9UT,ìIµ±æ"jJèÏH1NEF08:/M<!M@7I»¯R;/µ±æV8¬·/@A4M;@³ÁÙIµ±æHO"51ùª;¨6M<!

" & ( * # ! % $ )'f±x $$$$$$$$$$$$$$$$$$$$$$$$$$$$ Ò¬ ¡ w l »~s_Â $$$$$$$$$$$$$ Z¹tp ~U[`! ~U[¬ e ª n {'Borderline resectable Øj0¥,4=N@CKS)32 nab J<P
C;BQÁÎ\dÃÖÄ1§T¢ v"X\Ð034Öz^£r5k+-m¡ÖÔ1b¸'q­|¡Ój0¥,48S?QCMF/6KOERS1Ëz
0i,4OSDN\ºcv'Yj¿Å¶0¥,4³V®À¼®ÖÊo2>SJG9S¨Ä1b¸']µÕÏ¤¸¦«jh¯W0¥,4 FOLFOX ÖÄÁÎ7P
HE:SÍK#A5Î(-h²ÆÖÄ%DEBTACE&
1
§T¢

v

'¾\gj0)*4 microbiome 1ÇÑ®a"mI79
L#:#b¸5È+.

 °Ì

 $$ !

A:89#$%'&"
-,



}

´ $$ $

1BA.A.)(OK3.?740,
GF/<.C;Q.

 °y

× $$ !"

M6*A.(.JI@H)=+/-,EÉ u½© $$ !$

DR5P(,A.
=+/!?7-,·  $$ "#

2LA.A.)>N,.40J=+/-,.

> c · 5 T 8 [ X

1Borderline resectable ]>&R$*.4/137")(
nab 2-51,06UX:=VFN[W'S8PDB!
N9:YL&)*E[C;QA+?K#%J@GOE[MZ'<T½è

-°.

+& .ø6O8_ BRA =SÛE"¿Ô·5PEN Gem+nabpaclitaxel)GnP*íïy

5ÿT GnP û1 CRTTpÕÍSM9NêEJ!GnP Té/jgiPENjgi0)Gem%3//mg(m "nP%4/mg(m *=]jgi6)Gem%
2

20///mg(m2"nP%014mg(m2*WOÓäE"CTCAE b19N,µÅbözE"2+2i'iS¾9 dose escalation b¤9«ÞÜ07)MTD*bäEJ!D]SÒÃ4"=ÒÃS<B_pÕÍSM9NZûHNêEJ!#´T} MTD
Ujgi5)Gem%0///mg(m2"nP%0//mg(m2*PôäE"RD Ujgi4)Gem%7//mg(m2"nP%0//mg(m2*P
äEJ!ÒÃ4U7/-O"º¿;³"UðYG"¿Ô GnP û1 CRT UpÕS²¤{òO8_P£;]`J!

$ ! % #
®"ãÇ=S<9N|åÒÃTX>*tT©··5ÿO8_>"ÒÃßîS\_·5ÎÑU
YNø6O8^"'ªóÏØâwáU5#
6l"4ñÏØ4U0/#
3-SF@R90*!~&T²ÓOU"Resectable$BR =SÛE gemcitabine)GEM*û1¿Ô CRT b²¤EN<^"6

R·5ÎÑbý§EN?J !tþO BRA Ä:S<9Nvªó>¥4SðY]`)4ñ9Ðvªó4%56-*"·51*

ÎÑø6T¹R2uO8_CPb¸EJ1*!¾LN"÷ÝPEN\^Ë¤EJ BRA =S<B_·5ÎÑTÆSU"vçsÌTJYT\^8RÕÊ·5>õ2O8_P£;]`_!
ñTy

5ÿTËüS\^ GEM ßî·5\^Z+`JÕÊ·5}b¸FÚ­û1jdhk>óD`)FOLFIRINOX"gemcitabine(nabpaclitaxel*"ÒÃøò=SÛEN¡A19]`_\:SRL
N9_2*3*!D]S Katz ]U BR =bÛÅSEJ¿Ô·5PEN"mFOLFIRINOX S\_íïyÿP"I`S×A Capecitabine û1 CRT)4/#
3Gy*b²¤E"65R·5ÎÑbý§EN9_ !Gemcit4*

abine+nabpaclitaxel)GnP*SM9NU"Okada ]> BR =SÛF_¿Ôy5ÿPENý§EN9_ZTT "GnP û1¿Ô CRT SF_ý§UYN!E9!
5*#OU"BRA =bÛÅPE"¿Ô·5PENT GnP S\_íïyTpÕÏSM9NêF_CPb(åPEJ!ú¶åS"GnP S\_íïy

5ÿT GnP û1 CRT
5ÿ+GnP û1 CRT S\_¢»<}"¿Ô·5TÒÃ¿S<B_pÕÍ)¦ûÄ*SM9NZêEJ!
('")*
RIH\
NCCN guideline)Version 2"2014*S<B_ BR =T:K"BRA =PENqxTÖÂb$
JFÄ:bÛÅPEJ%m¹2ì&)CA"SMA"CHA*¼rVT»<ËæbðY_>¼07/,%$S
PQWLN<^"encasement bðYR9"n=ëùS<9N CA ¼rVT»<ËæbðYR9"o)&VTÈÁbðY_Ä:OU"¿åSÒÃª>{òO8_!
ITÙTÀPENU"mÔ·5>¤a`N9R9"n·5±ÔS÷3.Þ¯¨¬>cekf' |åSÈÁÍ=TÉà>

BR á|E²>N­ Gem+nabPTX ÌÚÎ¬ÝÏF¶g®2

u¹<A6N"dÉ CT EAÒM8D{©ÁlI?GÁ¬j¢PÀKD6"ex½©FË|P×<
D6"fÐ

©FyvI?Gk½Z^&b[V&PÀKD6!I?Í©nà¢ßE²<AG°C<A\_UVWRUXcYELN ERBD P>N:CC<?!
gemcitabine"nabpaclitaxel 3602-.4/175%(,'&!*
GnP ÌÚ­ CRT F protocol P§-E>!¾¿owÝÏC<A fulldose F GnP(GEM%-,,,mg'm "nP%-.1mg'm2)P-s/»Ø$-ÖB.R&`<?!¾¿owÝÏÜEr¯Çp
2P6 SD(stable disease)h¤F¢ßB"GnP ÌÚ CRT Hi<?!GnP ÌÚ CRT E76AG"Î¬ÝC<A/±¡ÏPÚ6A Total 2,Gy(.#0Gy x .1s%Õ1{)F¡P@?!Ì
ÚowÝÏC<AG"GnP P-s/»Ø$-ÖB.R&`<?(.R&`ÓG Day-F»
ØFJ)!GnP F»ØÞC<Aa]`-(GEM%0,,mg'm2"nP%1,mg'm2)8Ma]`3(GEM%-,,,
mg'm2"nP%-.1mg'm2)IBP«¹<(Æ-)"×t£PÇp<D9M¸¥F/*/`&`EL@A
dose escalation P6µ³ÚÞ(MTD)P¹<?!

¾¿owÝÏC<A GnP PÅÞ(-,,,mg'm2"-.1mg'm2)EA day-"4"-1E/»-TQR`EA.S&U>N!¾¿owÝÏEÇpP6"È¨¦¼PÀKD6¢ßE76A"GnP ÌÚ CRT P>N!CRT ÜE
º resectability FÇpP6"SD h¤B5@?¢ßE76A/+4{EP<?!
1" GnP 5803-.6/297&*,)(!+
4" GnP 58 CRT %#$' dose escalation+)*

gemcitabine#mg// m2 $

nabpaclitaxel#mg// m2 $

.
/
0
1
2
3

0,,
2,,
2,,
4,,
4,,
-,,,
-,,,

1,
1,
31
31
-,,
-,,
-.1

CRT Ü8M.+4{F´~}{·E resectability FÇpP6"SD h¤FqCÂ¹;O?
¢ßE²<P<?!ÄÛEm=AÔÑª"z½Ñª"Ê½ÑÌª(DPCAR)
FGÙ>N9"SMA ªPÛ>N¢ßGÃªC<?!

: O  Ñ F 5 J H

3.30(+2!1,0(+2!Doselimiting toxicityÏÃb{ÍG GnP EKMµ¹agÑÊvF GnP ÇÎ CRT FZ¦¡Fs³B5L"NCI Common
Terminology Criteria for Adverse Events%CTCAE&version/NÎ6AÃb=?2&!ÆÃb{ÍGyÕwc#Ë¥ÑzvF¢Ð#Ö¢E8<MZ¦¡C=?!Doselimiting toxicity%DLT&G[`FK7El°=?$T¾»¡x®ou"U Grade.[Fr¿u"V Grade.[F¨f%ªÌ"YG;&"W¤^>M%GCSF NÎ=AI,j[§;&Grade/x®ou"XagÑÊEm]>M-d[F CRT F®¬!
"
ËÒ

!

tE entry =µ¹agÑÊNe=?ÓG.3ÓB5@?%Â-&!.3Ó®3Ó:agÉ£ÑÊE\z=D9@?%-&$Tj¡½_%n=.&"Uk¶_#½_%n=-&"V Grade.¾%n=,&"Wp±%¸¯&%n=,&"X control |·D²ºÄFYa%n=,&!CRT E\z=?
.+Ó®,ÓB¤^>Mx®ouEKL CRT N®=?:"~LF-4ÓB GnP ÇÎagÉ£ÑÊNh=?!
.# '*-(!n=$%"

)-/*
¡È
¼Ô

p}
Õq

«iPQSR

Total"n=%&#' " $ #­¡
,2 % /0 &¡-, % 00 &median$10%.0'2/&-+ % 0. &)10(10,3 % /2 &´Å
-1 % 13 &,- % .- &©ÁÅmedian$.-%,4'10&/ % ,, &)-+(-+./ % 34 &yes,3 % /2 &-+ % 0. &noËÒ tE entry =µ¹agÑÊNe=?.3Ó®3ÓE86A GnP ÇÎagÉ£ÑÊE\z=D9@?*$Tj
¡½_%n=.&"Uk¶_#½_n6%À ILD&%n=-&
"V Grade.¾%n=,&"Wp±%¸¯&%n=,&"
X control |·D²ºÄFYa%n=,&!.3Ó®.+ÓE86A GnP agÉ£ÑÊNe=",ÓB¤^>Mx®ouE
KL CRT N®=?:**"~LF-4ÓB GnP ÇÎagÉ£ÑÊNh=?!
,# /+)&!n=$%"BR +NÄEX¡¾ Gem+nabPTX ëûî¼"ïOÇfÁ4

yÓúc_bN=AX©& entry ¶"MøxªNI<Jå1NQLTG!c_b1N=<J"/&K DLT*0wi«O CRT OËÉ+[ÙT"1&[ÌrDG? DLT [ÙTM>HGGTc_b2Nj
DG!c_b2KP1&Ë/&K DLT*Grade1¥á¦+[ÙTG?"ÌrO1&N=<J DLT P
ÙTM>HG!c_b3N=<JP1&Ë/&K DLT*ßÚ·Ë¦+[ÙTGGT"1&[ÌrDGLBZ DLT P/&*½mEXË¦+ORK;HGGTc_b4NjDG!c_b4N entry
DG1&Ë/&K DLT*Grade1Ø(|»+[ÙTGGT"1&[ÌrDGLBZ DLT [0&*Grade1õ¨·|z]`%d^\%#Grade1¯ýè±"0wi«O CRT OËÉ+KÙTGGT"c_b4*GEM$/...mg&m2"nP$/..mg&m2+[ MTD LàÏDG!FOt RD Pc_b3*GEM$6..mg&
m2"nP$/..mg&m2+LÏCYG!
+! GnP ,. CRT %"#&)$-'(*
Level
!+0,"

Level#!%" Level$!%" Level%!(" Level&!(" Level'!(" Level(!("*).Ë¶¦Þ¶¦
¥á¶¦
ç
ßÚ·Ë¦/*).õ¨·|z]`%d^\%
ß²#â²
íã
pÿ
¯ýÎp
g°
È÷©
Å|
·Ýn

/
0
.
.
.

1
0
.
.
.

2
3
.
.
.

4
4
/
.
.

1
2
.
/
/

4
4
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

.
.
.
.
.
.

/
.
.
.
/
.

.
.

.
.

.
.

.
.

.
.

.
.

!
¿16&O$§uLDJP"CRT &*n=1.+OÖ02&N=<J+¸£[DG*¸£!$6.-+ä¸£LMHG4&Oä¸£þùPipOÍWK;X$~Òj*n=/+"Ý,~Òj*n=/+"

¢´Ñ

*n=/+
"òÆÔöae^¹Òjü·*n=/+"éôÜ*n=/+"éº­lð³ü·*n=/+!CRTäLMHG6&Ë2&K¸£¡[DG!ä¸£LMHG2&Oä¸£þùPipOÍWK;X$ÝÒj*n=0+"~Òj*n=/+"¢´Ñ*n=/+!CRT NDG+¸£N'EXë©N

I<JP"ClavienDindo Grade IIIa Oë©[0&N=<JÙTG?¡'ñPÙTM>HG!+
l*P ISGPF Grade B [/&N=<JÙTG6+!
89:QKDG1.&N=<J"ä¸£LMHG4&["tLDJ PD LDG¬"Response
rate$45-"Disease control rate$6.-K;HG!

)OvÂ«Oìq!PËoÊK3/-*64'13-+

K;HG!CRT N¡[DG02&OæþÀ®{Ðae^¹Òjü·!P11-"R0 ¸£!P74-K;HG!pCR O1&[S7&*16-+N=<JÀ®{Ðk)P/.-ipLµÏCYG*Evans ê% Grade III&IV+ !
7+

!

"

óOtNUW BR +NÄEX¡¾"LDJO(GnP NUXÕ×q{"ï,GnP ëû CRT)Ph¿NsÛK;W"GnP ëû CRT N=AXµ¤û#P GEM$6..mg&m2"nP$/..mg&m2K;XB
L?CYG!óKPÃ@O©&KË¦?ÙTVYG?"$§ÐN}þsÛMc_bK;HG!

= \ô N 7 U R

5

CRT MÒëNëx°KCI­t®³'´îà¶Ï(=@WZY="hdg2M~Xá?W
ZF-öJ Grade/´îà¶[×SF="hdg1QJJOõ«±ënL´îà¶O×SWZL<GF!
Ueno WOq|Ío[Ú9¹¨àØøMÀDY GnP MVYÓÂ6&II ¿M;8I"Disease con-trol rate$50#-+"Response rate$14#
4+"PR QJNÆrÅ$0/Õ"Ù¾N¦©ñ'ÆrÅ($
0/#0+KãCI8Y-,(!GnP MVYt}ôåOÜ{ÌÃNÓMÙ¾N¦©w=ÑWZ"[ËDZPß³=·DY'progressive disease(¸=Ê8AK=¡BZI;X"§¼
Yh]ejKCIOÝ²MÁJ>YÒ¢[ëCI8YK:WZY!päJ§¼

ôMì8

ôMì8YMCI

O"nP MÒÈÌLëx°J7Yé¬¸zbf%ica%MVGI PS ÊsÏ[ïD¸MH8IÇnDYÞí=7Y!Von Hoff WO MPACT M;8I"Grade/m±Né¬¸zbf%ica%
Ù®QJN'ÆrÅ(O-0,ÕKãCI8Y0(!èN protocol Oê.kN GnP MVYÐÖt
}ôåKê1¤N GnP âì CRT [\J8Y="hdg2M~Xá?WZF-öMNR Grade/é¬¸zbf%ica%[×SF!/k[É:Y§¼ô[ºËCI8YAK[óCIT"é¬¸

zbf%ica%MVY PS ÊsMVGIø¹¨=ÔKLY¸OÊ8KÛÄBZY="®öMVGIO nP Nª[óDYÏNµ¥Lð=ÞíJ7YK:WZY!GnP âì CRT Nø¹¨M;
8IT"IVR MVYuô[ÞíKCF®öO.ö×SF="£§÷æöO×SI;WEl½M
vØJ7YK:WZY!
! $ # "BR ø
L'ÒM BRA(MÀDY GnP MVYÐÖt}ôå)GnP âì CRT MVY§¼

ôåN-HJ7Y:WZY!èMVX GnP âì CRT MVY§¼

ôN RD =ËBZ"yC

Il½MvØJ7YAK=¡BZF!Î_j`%JOè protocol [d%^MC"BR øâì§¼ CRT N

ô»òOëç
MÀDY GnPôw[¯DYÂ II ¿[GI8Y!
&%-(Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and longterm
outcomes among patients with resected pancreatic cancer : the CONKO001 randomized trial.
JAMA 310'14($-03/*4-".,-/#.(Takahashi H, Akita H, Tomokuni A, et al. Preoperative Gemcitabinebased Chemoradiation Therapy for Borderline Resectable Pancreatic Cancer : Impact of Venous and Arterial Involvement
Status on Surgical Outcome and Pattern of Recurrence. Ann Surg 264'6($-,5-*3".,-2#/(Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364'19($-4-3*.1".,--#
0(Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nabpaclitaxel
plus gemcitabine. N Engl J Med 369'18($-25-*3,/".,-/#
1(Katz MH, Shi Q, Ahmad SA, et al. Preoperative Modified FOLFIRINOX Treatment Followed by
CapecitabineBased Chemoradiation for Borderline Resectable Pancreatic Cancer : Alliance forClinical Trials in Oncology Trial A021101. JAMA Surg 151'8($e-2--/3".,-2#
2(Okada KI, Hirono S, Kawai M, et al. Phase I Study of NabPaclitaxel plus Gemcitabine as Neoadjuvant Therapy for Borderline Resectable Pancreatic Cancer. Anticancer Res 37'2($41/*4".,-3#
3(NCI Common Terminology Criteria for Adverse Events'CTCAE(v.4. Available at : http : //evs.
nci.nih.gov/ftp1/CTCAE/About.html.
4(Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula : an international study

6

BR C40</28: Gem+nabPTX >A?79B@1=3;65

group$ISGPF%definition. Surgery 138$1%#-&(*!)''+".%Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy
for adenocarcinoma of the pancreas. Arch Surg 127$11%#(**+&.!(..)"('%Ueno H, Ikeda M, Ueno M, et al. Phase I/II study of nabpaclitaxel plus gemcitabine for chemotherapynaive Japanese patients with metastatic pancreatic cancer. Cancer Chemother Pharmacol 77$3%#+.+&,'*!)'(,"

6 Y ¯ - I 1 R N

7

8=B;>@E?7#A!%'3(1).,"&-0+23$
D:>#6!%03*/4C5<9Ëð)(% !JÅåÆÎ+ÌH×=Vy«²íIÕ¬ÉìÜsÑ®E1V!\r`pdmiFZkofqrJ
2>WPZriq_r#Zriq_r³*Öa^jpXd%_ehF<A¾ÃÚIlpnr-ýE1V!:WTI'§Jö;WA.¹®6G8".¹º"ÍÝä6ODï<2PIFGCD2V!,§Xö=V:FHSCD"(ÆQîã6%T5FGU"¢¦æG][io[r¨ÇI£FGVS3G\kgrb6Ïµ;WV:F6Ø;WV!

# ! $ "
ñ!H49VáÆItÆ¾ÈúHSV­ÿÂJ&,,"ÀE"?I3BÎ+ÌJ/(XÊOD2V!÷
ò~ItÆ¾ÈúHSV­ÿF<DJ¤PÕ2!1°ÂJ,*+0óHJáÆH42DÜ-vFGVF)Ð;W"­ÿÂ"1ÂFPHÓ}IzêXßCD2V))!Î+ÌIÓ½JZriq_rHwÔ<D2V:F5T"Zriq_r¸-ý&androgendeprivation therapy$ADT'HSCDZriq_
r³*Ö&androgen receptor$AR'a^jpX±à=V:FE<KT8JÄE7V+','!ADT J·¿

MAJèxÆÎ+ÌH×=Vø¶æG¯-ýF<D+<D2V-'!<5<"2>WJ ADT 6$

G¼ÙE1VÅåÆÎ+Ì&castrationresistant prostate cancer$CRPC'FGV.'!\r`p
dmiFZkofqrJ CRPC H×=Vø¶æ¯-'E1V!CRPC FGCDPªÔ=V AR a^jp
HSCD¥þIÓ½#Æô6ûAWD2V:F5T&Á+'":WTI'§J;TH AR a^jpX±à=V:FHSCDXõ=V!:WTI¾'§J headtohead Eö;WA.¹®6G8".¹º"'§IÍÝ#ä6ODï<2PIFGCD2V!!EJ":WT,§I(ÆXö
=V:FHSCD"?W@WIvâù9QîãX%T5H=V!
))¢+õýÀ¢+6Ycrd%6Y×©»ücrd%http://ganjoho.jp/reg_stat/statistics/stat/index.html%! CRPC "#$'&u|IÍÝ¶X=LD#A<"¸¶I2>WHPë<G2°Xé0ç/F=V!
)ÞÛÛ{y'ûÒ¡~ ÷ò´æ¯-·Í¸Àñ¿KÇBV\r^oakgIZimdqrLî¸KBVmrbl{Û¦

8%&"#0#ÝðÎKÀñ¿LÌ±É=@WG:V"tzHÌ@WV CRPC ¨!
!Âd_f_dqrÊ-4/ng&dl!0©

t°9>DÀñ¿Õv(prostatespecific antigen%PSA)ÃÌÊ=1öÄH°­"<FÚÌK£ïBVÊ= nadir SU1ng&dl t°°­1#Á²ÎJ»éÎ¡å¸=Yíáóä=J@WG:J:¨!

2#1/t°L¨!
3#ECOG L performance status(PS)=/+1L¨!
4#Ï¼JØXîBV¨H"tzLªXBPGèDB?I!
!ÂinoirÊ.0#
4,¥½ªÊ°(upper limit of normal%ULN)!AST ;SN ALT.1#
4,ULN(DEA"Ðw¨HM.4#/,ULN IBV!)!¸Ù®=J:?I!à¶Ëò=J:?I
5#Ï¼J´ØXîBV¨H"tzLªXèDB?I!
!¹]pZchrÊ.1#/,ULN
6#2}t°LºÅ=QWV¨!
7#¾êâ«KSU"ç³<T¢|OLÓu=ÔTWG:V¨!
$!"#
0#\r^oakg"ZimdqrQDMjpgh`qrKÇA~Þ®LyõL9V¨!
1#§æL9V¨!
2#CLÆ"ÈÑx¤=çô¬¦LÇ¯¨IAGßÏÑH9VIÖRD¨!
$"&%#!
0#ìÎ%·Í¸Àñ¿KÇBV\r^oakgóäIZimdqr*jpgh`qróäLî¸$sÁ¸LÛÒ!
1#¦

%1/03×00'1/08×0/!

2#¦e^[r%Üëmrbl{ãÛ¦(µ1"2)!

%! $#"&

: \ ê  L 5 T P

9+" '%)!$&(#*,/#îJM¥°ó$^sgôµsEK PSA Õa[CACµ&KÅ'1/®ªíH"1/®:3ý§LOCMÙt§LK¦^@YG8W"¹+{LJÅ®§såÉ1Lªí!
0#gPø%$¤¸,++"º-++!
1#Prs$q%nmn%:«BX Web Pikp~K^dmkAGÉ7EPrì!
2#¨jF)ã$_'2+×zy&2+×ù("PS'+),&-("N8¯'JAOCMÑNLP&Ñ¢LN5W("å-!
3#îhÌ$HJ²@YX PSA 7OHL±¬!

!,.ñËKbJ@YC PSA K86G"PSA IHMÖ=Iè9V"
fIHMz%k`
9V-0*ù9E-ng&dl ùùöA"ùö:^QVYC\9V.ñ¬ù¹ACèOHLÕ:J»RUH5DCûÏ[ PSA 7IJ²A"PSA 7:¦JACI;!
4#méLhÌ$2*;±¬"6bJ'CT xM MRI ´NÑkc(K°F<}7*;±¬"
Ùtõ£'§sâOHL±¬"PS :,B¡ùBXOHL±¬"®'HK<BXbwb`sáOHL±¬"PSA 4Ã"êL2'"QOL!
,+#AÜLhÌ$[éêLï"XJL[éê'docetaxel(ILDésK8=X OS T!
,,#UMIN æ¿ ID$UMIN++++,00-4!
,-#æ¿ßå-$·@="ÄQ="÷=ÇSuði"Y½="Ýv="Þò="nQ½
="à="~Áä="ëçQ="·@=",.½Ei"kà½Ei"nØ*i"ÄQäÓä|i"úÆ*i!
!

"-+,0_-¼-0\K>,LP:ÉZYC!-+,0_/¼,4\KMßå-:VKACkn%r^oy}%p_e:

Ô@YC!-+,1_/¼",+¼"-+,2_/¼",+¼KMyek}%p_e[É6"#Gü¶[qÐBXIIRK"øP9#K­AG³@YC!e]¯®êLÖÿLC¾[WJ:V"wæ¿L²[!<AGRV7LH"q%n|u%j%pNKe]¯®Lackv%
rLÊRÉZY"Í<h@YC!ÒÂRc_?IL

Ô[JAG6X!OC",)-¼?ILt

%ln%L`þ[É7>IHÖÿL#Gü¶[J±LKqÐA"øP[9AG6X!>YOHK-,ÎaÉ'email KG(@YC!"EKæ¿ºSªí0?°óKK^dmkH;XU7{fordyrh[Û(A"¤å-K`lAC!-+,1_0¼KMyrho[ BMC Cancer'-+,1`

vdrx]dn%.#-33(KRÈA"-+,2_4¼K^dmyr@YC0(!-+,2_,,¼,\ÀÚ,,/:P@YG8W"æ¿±¬ZLP©:5@YX'$/(!

»Õ¼Áð¿JÊAT[q^oakeHXfmcpqKì¼JATmqbl{àª

10

2$ 67'0:8<1+!3.(4;*#,)/&"

2% -59'8<1+"!

Å¹Ï×êÆt½È'radiographic progressionfree survival%rPFS(HÂ½È'overall
survival%OS(W]gmZjn[qeiZqdH?C"e`a\`oÁK¯:Ê´KXfmcpqKÌ
sÄª'COU-*,ª(GL"gm`hHà?ìwJ rPFS"OS WyÒ?C!PSA êÆt0(
JE5FOìwJyÒ?C'HR*#.3"ÑzÐ++#
+vs/#
0(
![q^oakeJ?FOÚ@<ÌsÄª:VU'PREVAIL ª("gm`hHà? rPFS"OS HOJìwJíWyÒ?C!PSA
1(êÆtJE5FOìwJyÒ?C'HR*#+3"ÑzÐ++#
,vs,#
2(
!?9?"ñ§LÓ¾à?

C:I5µJ"¢Ë¼:ç
T>UF8S"®ó³µ"ë§KÀÍ$Ô:Û?5OKHIDF5!ÜéGLHà?",«$-«vKrYqc&_òèWDF5T=H:É<"Xfmc

2(
3(

pqP[q^oakeK~LÔ×G4T}Ý¼O©Ö>UF5T+*(!MC"ªK¬ò:É¥G4
TÜéK¸9R"OS GLë§Kì¼Wâ|?:C5}Ý¼O7RUT!COU-*,ªP PREVAIL ªL rPFS P OS WgmZjn[qeiZqdH?F5C:"ÙôK¦Kã»KºL PSA º
KNK¶:.-)GÅ×ºKNK¶LVB9+-)G4S"PSA GKã»Kâ|:QSxåG4T}Ý¼:­¡>UT1(!ÆtWÃJ²AT=H:±îG4S"Ü·ó³KµG PSA £:æGu|9EÎ5

G7TKJÊ?"rPFS JáîIÅ¹ÏèL°Ç;:ß¨G|9EäÞJL7I

5=H9R"ÜéGL PSA êÆtWgmZjn[qeiZqdH?FªW6=H:¤OïJØ
DF5TH7C!

7 Q x  E 2 J H

11! $ # "
jgDK@A"rE7L6DCM"oqCTRWYRZtEphBCNK4CSXVZ
UEz7e;ON!jgFdi6LEjgD[<C3"|7;O>EbvkB<

A_E2NIEBn5A3N!
jgE\fP:`3>?8":u^PwMG<>m]s7QycxjgsEaD"}KMl~<{9G=!
&%)&Schally AV, Arimura A, Kastin AJ, et al : Gonadotropinreleasing hormone : one polypeptide regulates secretion of luteinizing and folliclestimulating hormones. Science 173$)(+.'0")1/)#*&Labrie F, Dupont A, Belanger A, et al : New hormonal therapy in prostatic carcinoma : combined
treatment with an LHRH agonist and an antiandrogen. Clin Invest Med 5$*./'/-")10*#+&Akaza H, Hinotsu S, Usami M, et al : Combined androgen blockade with bicalutamide for advanced
prostate cancer : longterm followup of a phase 3, doubleblind, randomized study for survival.
Cancer 115$+,+/',-"*((1#,&Mizokami A, Namiki M : Reconsideration of progression to CRPC during androgen deprivation
therapy. J Steroid Biochem Mol Biol 145$).,'/)"*()-#-&Izumi K, Mizokami A, Namiki M, et al : Enzalutamide versus abiraterone as a firstline endocrine
therapy for castrationresistant prostate cancer%ENABLE study for PCa&: a study protocol for a
multicenter randomized phase III trial. BMC Cancer 17$.//"*()/#.&Ryan CJ, Smith MR, de Bono JS, et al : Abiraterone in metastatic prostate cancer without previous
chemotherapy. N Engl J Med 368$)+0',0"*()+#/&Beer TM, Armstrong AJ, Rathkopf DE, et al : Enzalutamide in metastatic prostate cancer before
chemotherapy. N Engl J Med 371$,*,'++"*(),#
0&Sartor O, Gillessen S : Treatment sequencing in metastatic castrateresistant prostate cancer.
Asian J Androl 16$,*.'+)"*(),#
1&Terada N, Maughan BL, Akamatsu S, et al : Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapynaive castrationresistant prostate cancer : The Kyoto
Baltimore collaboration. Int J Urol 24$,,)'0"*()/#)(&Mizokami A, Kadono Y, Kitagawa Y, et al : Therapies for castrationresistant prostate cancer in a
new era : The indication of vintage hormonal therapy, chemotherapy and the new medicines. Int J
Urol 24$-..'/*"*()/#

12¢ctVÞO6C^Q~IfÑ\IÖ|¨Tjyrqfy÷>oPY,.;>82"4!%7+6<0:61@?/$'*)(&*35=#-9öL¾+&% ctVÞQ¢KÇ^M7ISÖNKÊYØK2]"EPÈbQãN;K2^!¢Q$NKÊY°ØaL^8"$Q("é_U#ÊY¢)L34SL::]KAJ|eoaYAJ9Fâ82^LÄ5"K±>LOQ~INP´©nOQºfÑaOGAJ=_a+C^%aÃAAF!EPCLAJÆHFK±Q~IN Transcriptome !O[]ctKÊYìKQ~IOÇY¹AJ3^fÑ8dûQG?_F8"=PB7\Ö\IOJC^tF®=XK2^ synaptotagmin 13&SYT13'a¸'A"ÖP-¿Ma1C^jyrqfy÷
>oPLgÆAJ´©aøXJ9F!udkctVÞvoxO6C^ siRNA cÅRNa¡XFs´©P²7\"
SYT-/Q¢ctVÞO6C^,|N\TO÷>oYP~rN\IfÑK2^=L8×?_F!

# ! $ "
¢QsqKQ|(LAJ^M8Ç3!¢Q¬æOLMV^?K2_RRÒ«I2^3QI"
éO[]ÁN¼8¤7K9^8"SLFTKaZ4L¼_NÙLN^-'!N7KYctVÞQ¢KØP1,*{îa$X^LLYO"ËYSÖüP]8K2^!ÉÖI]j"éQ_UK2]"mÛ&oYv¿K2^!EPFXo8ÖPBòLNHJ3^8"EP¿Q9`XJº
GIK2]"SÖücúZDhÌa±J¼_NK¦aFM^.'!
¢O6Ak¶JLNHJ3^fÑ\IÖ|Q"ramucirumab L HER2 ü¢O6C^ trastuzumab O"ylemitcyp+| nivolumab PWK2^8"s´©O[]=Pïªa5WAF
3!¢P¼O:9:`^ÊYK°ØLAJctK"wyr#K"³ÆüKL34):üÚ

8~N^8M_YãN/IPK±83ÏC^=LK@\_^-'!Ka~C^¢Q Stage IV¢LAJAJz`_J6]"K±OQ~IN÷>u%g%ZfÑ\IÖ|QULbM3ÏA
N3!s´©KQ"ÞK°ØN3AQK±OQ~INfÑþeI¥èPxaFB"¢KQ
O4:µ\_"SÖNKÊY°ØK2^ctKOQAFfÑ\ILEPÖ|aµäC=La{\
LAF!
K.Q4:PfÑ8

C^4?PHa±J°ý?_^=L8@\_J3^8"EPBOQK±OQ~INfÑ83ÏC^LPÄ5n82^/'!$Q=PnÀüK´©aøX^=L8óFN¢ctVÞÖYP¯¥LN]P^LÄ5F!VF"+C^=LKÖ¿8¤7K9^Ö\IfÑaYC^LOÔO"àüP2^ÜP'iOÓC^jyrqfy÷>o8YK9_R}§ô3!E
=K"õÿÜ\QVDÖ#÷>PzKh%LN]4^½lfÑa<ÐC^FXO"Stage III KOPå¼lçoaà;J3N8\ÊY°ØP~N^4­P¢·Y.*ña6íLAF transcriptome !aÆHF&ù-'!EP²"ctVÞÊYPWK~}NY¹øa×AFfÑLAJá3î
<F synaptotagmin 13&SYT13'Qêp}/E#tF®=XK2]0'"?V@VN0ðÑaAF
ßÍpP0ðZÂ¢ÎP9ÝO

AJ3^Uü82^=L8[xAFFX"uIN½lfÑL[>A"ÕPknmsK2^Y¹#¥U!OøbG!

+w»:a`2]ë£T

. I { ½ < ) B @13

3! 7.0?9-6$ Transcriptome /4

#
¶¼

$

^¡z©rc;CEo04]k®´§j¿¯zs±8)F SYT13 <w:©r#l¦c

Hv+?/"[`<pmHv54!
0!6;BU9;)JG%"$ SYT13 '<P8I]kw³f;07"SYT13 <SPKOJZ|qHv+!SPKOJZ= siRNA ²;CEv*"w³f<¦$WST8 assay%"

²$Matrigel invasion assay%"¸¦$Wound healing assay%H«

a04!
1!SYT13 ':XTD'>CPCR array"Antibody array ;CE SYT13 9g1F~»kj¿¯zH¶¼;y04!

2!-*+SVQE.,/&J#( SYT13 N5L siRNA SAOMW'@7
MKNluc Hº*7UJM®´§VQXHx0"SYT13 ;1F siRNA ®u¥£¹$&d"(i%<®´§netbHo¤04!in vivo imaging ²$IVIS%;CE¬HVRNWZL04$&%!

3" *'(<=;2+),%5#& SYT13 9-6 siRNA <1:8>

3!SYT13 R?'HKL4='>F]kh}-D04]o$k­,C>ªk­%"®oH;"¾

PCR ²;C57

SYT13 mRNA ©r¢H?4!];6*7=°Hº*7 SYT13 <µ_Hv*"¨Y
TX8<©rcAv54!
!

"

0!6;BU9;)JG%"$ SYT13 '<P8I
SYT13 <SPKOJZ;CE"]kw³f<¦" ¦"¸¦=2G3G·\;`04$'%!

14LTz~vb3o-<sJq{]yq_U6AHED?Hgp|4Ow

8" SYT13 .-+,*/&()034=':6;!75;!>9;'<1#!SYT13 "$)('"%&'&b4TS{]>qNl-< PCR array 0"SYT13 wW5cZ}4fd9exR

KX3S

-< GSK3B"NOTCH1 1I2k4nS>u8.!7."Z}tB@CGV>yq1,. Antibody
array 0"SYT13 mP3:; ERK1#2STAT3 pathway"HSP27"GSK3B 4FH\M)i+=.!*
4:(3"SYT13 5cZ}4Qr3[-<a2{]1rj>^/*1)`Y+=.$h&%!

8# SYT13 $2?%) signaling pathways

0 K v ½ @ , E C

15,!)&'AB?6*(+#9"% SYT13 =/; siRNA A5><C$40
OLM®±§xPNQJ¸-: SYT13 ?5H siRNA ®o¤¡·$y(\"*y_%@®±§xg]nZJj¢48!¥b>®±§xgA"siRNA ¡·f;²?º3I:-8$)%!In
vivo imaging system$IVIS%;®±§xg@hu¯WJªX5H<"siRNA ¡·f;A®±§x@p0²?]3I:.G$*%"7@iZOLM@c_AµR?V48!

4! *$'8:72+(,#6.530

4" *$'8:72+(,# IVIS &%),;#/159--!SYT13 @3$8:;.1$27
S|Jp98SaÁ/F£8@ SYT13 mRNA ¨l¿J¿ PCR °;48!®±§x@¨?5H ROC e[?.-:Sak¨@ SYT13 mRNA ¨l¿A Area under the curve0&#+')<q-`Jw48!B8"SYT13 q¨lf;A"v´|{m@À®±§x¨¼0µR?q1"Sa SYT13 ¨lAq-®±§x¦Jµ5H@C>F6"}»>®±§xs¨¶¦Dµ5H2<0w3I8!³UW^°;D"a­ SYT13 ¹Á;A®±§xs¨«

0

q1"¤tdjru@jj>=@~¿@j/FD©Y¦;,H2<0w3I8!3F?"®
oT/FD SYT13 mRNA @jz0Y¦;,G"SYT13 ¹ÁAµR?®±§x@«m¬¾;,98!

0q1"¶

}*3ýÄPåC\ø{ñ-»%ñ¼A7SgxoncxÖé0Qþ

16

'

%

}*3ýÄR"äê_¡G+¸:JõñOqwjiL5["ä;O-»;·<BK6\!BG;I
K"çhfmu¡FQÙª;$DBX¾9©_ïC\XQLRO="*3ýÄÚ_º\-»Û,ñËQ4R"ÐP²úL5\!û"ÖA§ÏP96K"conversion ÃÈ"ß×ù

A0"*®

A0ON_áV°^EGÅñ¼APY[íÛã_÷\}*3ýÄÍC_¡¦C\!B:B"

æ)-QÀRzÞMBKÙª(üO}*3ýÄ&/QØ¯PY[9©(BO¡_GNIK9["Öé9YS¼AQ@5P96Kpvaeiu';2U]K6\!
±"&;öïBG SYT13 R*3ýÄQãµ_#Ìó|Qê:Z£ÇB7\'O-»r'd'
MBKÖé"³þsnktxf"¼A«ÿïQ6D]QÏ°P96KX8<L5["¨.

~AQ¿§P¬>KÆ=O¥MO\!AZP"FQâ;¼A«_½BG@MPY["¼AþM675P96K
X82L5\!&Q¿¦LR´1Q*®ù|ÒPY[?BGrbi*3ýÄslu_<6K6\!@QÑL"SYT13 PåC\ø{ñ siRNA ô:;*3ýÄ¢ÝÚâ«_½BG@M:Z"
SYT13 Q*3ýÄÚP96K´1Q*®ù#Ì(î¹à"î>)TQò"*3ì!´1TQÛëMÓÉQðLÂG\6_8BK6\XQM­8Z]G!
! $ # "
ó|¡Fø{ñO Transcriptome ÜPY[öïBG}*3ýÄE-» SYT13 RÖé$¼AQ@
5P96K82O%ñ-»L5\@M;½A]G!±©"SYT13 _%ñMBG}*3ýÄ-»%ñ¼AQþ_ØWK6<G6M­8K6\!
@QÏ_9Á[BK"¤ÊÚ_6GH6G;`Åñ¼A¤¶èQyPÔ=ªD_ÕBÎ?
UC!
(

&

,)Van Cutsem E, Sagaert X, Topal B, et al : Gastric cancer. Lancet 388%-10/*1/"-+,1#-)Shen L, Shan YS, Hu HM, et al : Management of gastric cancer in Asia : resourcestratified guidelines. Lancet Oncol 14%e0.0*/2"-+,.#.)Kanda M, Kodera Y : Molecular mechanisms of peritoneal dissemination in gastric cancer. World J
Gastroenterol 22%13-4*/+"-+,1#/)von Poser C, Sudhof TC : Synaptotagmin 13 : structure and expression of a novel synaptotagmin.
Eur J Cell Biol 80%/,*2"-++,#

= a Ã Q Q 8 X U

17><5HPOAICE76F4'B%)
FOLFOX QKJN+1/.,2M;=0!-*N$&
6GL9?QK"DEBTACE#(D3@:8E§

6ö,&% ,"ôüRïDL;["@>P;@\ôüQ,VýáÀ?MR"ößM1z"ÌßMR.zNOJL9\!
G]P09"Û±ôü"øMWôü#|R¨úPïDL9\!,QÈ"ÃQ"(PQ=QÛ9PY[åÎ .ôü#|PòE\H¬R"éDKK8\!OKñ/#|QH¬R"¸ÃåÎ¬M8JLWì¹/U=ñ
?"GQH¬WCI5RM8["Q=Q­W«ÿ"M8\×´=ñ9!,"8MåÎ5.ôü#|PòE\bsnkeuÙo&h`J9H%DºçQ=(DEBIRITACE)QGJß=ñÞ;µC]L9\!TH"DEBIRI
TACE N3ÊÃQQ FOLFOX Q=N`7JCFHTÐÁ©Mwêß=;µC]L9\!·_]_]R"FOLFOX Q=
7JbsnkeuÙo&h`J9H%DºçQ=(DEBTACE)Qwêß`4E\TÐÁ©`NxDH!SL{~QÑ+`'LÕUQcums&`¾D"ª¼ÕUÈãøM8\!

# ! $ "
,"ôüRïDL;["@>P;@\ôüQ,VýáÀ?MR"ößM1z"ÌßMR.zN
OJL9\!TH"ôüPY\,À?ÆÞR/--2,PR,0#
6BÜM8JH="/-.2,PR3BÜPQS\NÝÿC]L9\!G]P09"Û±ôü"øMWôü#|R¨úPïDL9\!,QÈ"ÃQ"(PQ=QÛ9PY[åÎ.ôü#|PòE\H¬R"éDKK8\!%R"OKñ/#|QH¬R"¸ÃåÎ¬M8JLWì¹/U=ñ?"GQH¬WCI5RM8["Q=Q­W«ÿ"M8\BN`;µDL>H.)!OKñ/#|ÕUQH¬`éE\HVPR"Y[G­O:ËQ=Q/=óC]\!
ôü#|PòE\ek&ktÃQR"¶*Myè<Z±_]L;["Kemeny ZR/--3,P

FUDR Q%ùN 5FU+LV êÚQ=Qruiq1Á©`±9"ë­M(14+"/1+)"êâð(/1#
1e¤"/-e¤)N%ù=êÚQ=`Ö\¢`ÄDL9\/)!@><ZR"5FU `Ç.2Â<@L%ùE\ÃQ=PY[ë­M2/*50+"êâð.5#
3*/3e¤N;µC]L9\!
D<DO=Z"FOLFOX"FOLFIRI Q==3ÊQ=NDLNC]Hy²Q 5FU %ùQ=
QàäPR«=8["%=Å¿DHñ¿æ&¬^®>¥MR#|Që­MR.5+M8JH!)
R}ôMR/--5,<Z/-.-,QP FOLFOX Q=!¯ßôü#|òE\fgprjuN2Ïlupu`J9H%DºçQ=(TACE)Qõ7'víTÐÁ©`Å¿D"³9ë­MNH¬Qþ='Z]\BN`;µDH!,"8M TACE PJ9\Ø£ºç½PNDLQF»IÉßo&h=/C]"åÎ5.ôü#|PòE\bsnkeuÙo&h`J9H TACE QwêßNGJß=
ñÞ;µC]L9\0)*6)!F»IÉßo&hQ(ûNDL"bdu÷CFH¯=a»=Í<C]\H
V"AÓ£ø-$QÖÒR¡2M8\BN=AZ]"êÚQ=NQ7J=.M8\N°:Z]\!

B]TMPbsnkeuÙo&hPY\ TACE N3ÊÃQQ FOLFOX Q=N`7JCFHTÐÁ
©Mwêß=;µC]L9\0)!
,)R¦N}ô Ô$î´Ü³$04M#DW\tkg^xgÊãm%e:a¸ìo^N%yö¿ª18}ÕNH¥YSKM"éÏGni!L$04M#DWÚGLÂo^NLYc2M"FOLFOXo^Yh\tkg^xgÊãm%eYh:G:a¸ìo^'DEBTACE(N%8ö¿ªYl|CG!
_¨JO"éÏGni!L$04M#DW FOLFOX o^Yh\tkg^xgÊãm%eYh:G:a¸ìo^'DEBTACE(N{óãYRDWAKYc2KDW!£"2MO"ÕÂoN DLT
L¬µY Primary endpoint KC"Secondary endpoints KCI"eÀÓ"õ¯k"S\M#DW
õ¯k"bùzåþ"óåþ"\tkg^xK SN38 N¦-F7"Æt"èN\kYë1
CG!
"

!

#ÓOéÏGni!L$04ÒpJ"}Nð&Ì"ÏÌMTVð[DW!
"!),*+%'.(ô×2MïJ9WAK>DBXGÒp
/(éÏGLni!L'1^Í}Õ($04'.ß"udYÏ?(0(Eq /-¹}Õ
1(Performance status'ECOG($-)/
2(Response Evaluation Criteria in Solid Tumor'RECIST(9W:O modified RECIST NQ2S\Mµ,DWý1GS\YMeDWÒp'»øds\d°N/J}Õ(3(ÅjúG>ÈW]ÁBXI:WÒp
K¦âQGO±-â, 0"---&mm3QGO , ."2--&mm3¦ÐOâ, 4#
2*.-1&mm3

AST'GOT(+ ½ëÌ+Õ­N2J

ALT'GPT(+ ½ëÌ+Õ­N2J

÷mtumx+ /#2mg&dL¦ä`vZfjx+ .#/mg&dL4(PªÄ_Ý=UXÎMTW;~N=UXGÒp
#!($&'.(2)<·§Ë9W:O?¾¢2)ÂoN

>9W!

/(´7N:a)dacqxhQGO:a)çacqxh>9W!
0(´7N¡"Vá/mÒp1(Ñ=UNÚñÊ¦p2(axhw%uTGLíÒYeDWÒp''C"7¤][udãO

fDW(!

3(É>LµYÒ'0`s"0Z¸"ÃãI"IîàÒ"axhw%u¶@L9BS"ÙTó"Þ
Tó"²\"Tó(YeDWÒp
4(ÉÒNæÛÔN9WÒp
5(CUSC?OCØCI:WGãN9WÒp<TPÇAU
6(®¶@YM;r%iûºZvu_%NYeDWÒp.-(û CT 9W:O¦ûJ:aNZ¸>©UXW!'«üKCI6ròNûCT JN1DW>"N1¶@LÖµO¦û'tb%l% DSA SR(JN1DW!
..(UGT1A1 M<@W/HN5¼!¤'UGT1A1*6"UGT1A1*28(Yopêµ"QGO:EXSng
wêµ"KCISHÒp
./(FNÿ(8>_¿ªN#ÓMT38KN*CGÒp; [  ò K 5 T P

!

19

"

$!637J,C1
åJ9=XòL"·¯u}òäKïä"ïóLÌ?"Óèu}¶òäJ9=Xe&a
J®>BX\hdb]lKïóZºv@XSKH@X!ÖîLntKÊWH@X!
%!7JFGÓèu}¶òä(TACE)%Îpã¸Z¼ªJ\hdb]lZ®>BDe&aZÓèÖJÒ
í@X!Òí¡ñL"microsphere 1V Z·óÒí?DÏ5X6LÓè;Ë¾?DÏH@X!TACE
Z1¢æ"FOLFOX òäJUX·¯u}òäZ.¢æJÒí@X(â-)!1¢Z-^&iH?
F"/^&i@X!1¢Z-_&`H?F"/_&`7!5FU KÒíóL1,mg ÂoG´W

FX!

," *-&$%'!(TACE Z1¢æ"FOLFOX òäJUX·¯u}òäZ.¢æJÒí@X!
1¢Z-^&iH?F"/^&i@X!

&!HCDM<L>ìÌÑö©ô±L3éH?"Ñö

-Ú"È³

-Ú"¹

.ÚHµÌ?D!

'!TACE +)*/5BAIK"MTD#,=C).-=;IK"RD#,2C8:
jgi-:Vy@X!{jgiJ96FOA/ôJÒí?"-ôS DLT ;ØRVYI6¬L"
KjgiN°Q!/ôÆ-ôJ DLT ;ØRVYD¬L"ÔjgiG/ôÈv?"2ôÆK DLT Ü;.ôntK¬JL"KjgiN°Q!/ôÆ.ô5X6L2ôÆ/ôn«J DLT ;Ü?D¬
JL"CKÒíóZ¿½îó(MTD%Maximum Tolerated Dose)H@X!À?"jgi-G/ôÆ.ô5X6L2ôÆ/ôn«J DLT ;Ü?D¬Ljgi(*-)J°Q!jgi(*-)G DLT;|Ø>YD¬LåZÆ@X!OD"DLT ÜKÞÌL"fkc_&iò~ñôKPZ¼ª
J6"fkc_&iòÆôGLÞÌ?I6SKH@X!
Level *- % 4+ 1,mg'1V(.ml)
Level- % 4+-,,mg'1V(.ml)

Level. % 4+-1,mg'1V(.ml)

Level/ % 4+.,,mg'1V(.ml)(!TACE +)*/IK?4E@"DLT#09(â.),# DLT )+!0×»@X Grade0KÆ§(1,,'mm3)!
,,,'mm3)!
!Grade0K¦ß§(.1"!AST'ALT «¨ Grade0;-¢n«»<!
,mg'dL ZÇ8X!
!T.Bil ;1#!IVR"ÖÍ¤ÅODLzwÍ¤ÅZð@XÛù$Ãs!
!Grade/n«KárÕ²(À?"PD JUXSK"àõ$ÜÙ$m­$÷Ð$øÉ"MÁêL¥<)!TACE JqBA"FOLFOX JÝ7Õ²HÞÄ>YD¬L"DLT HBA"FOLFOXZó?F_&`Nn@X)!
-xëK FOLFOX òäKy£ZçD>A"FOLFOX òäJp?I:ED¬!

Þ·ñú"PïC[_pig`tKÒàj$d(DºãQ@Qò}èÇ°20

DLT ¾R1b$c'2b$cÁæ-UL(MB"C[!GHB"

Q DLT ÓP&BGÛ¹^ DLT M

P&BKW"+àMËQMQ¨<8ýL=[Û¹R DLT MR6öBO9!

UG"RD Q¬ýR"2b$c~¸QÑ*OGÈÙW¿¶MBé¹ÿP6öC[!DLT <5áBKW")kshb$qËQøÅQÓ*P&BO9³ZRkshb$qËQ^ªìC[!
"!08'-*1'<3(
3" 1'/5(,)0

4­¤UGRµø¤ . 3"000%mm3UGR1"
500%mm3
3­Õ7 . 65"000%mmT.Bil- 2#
5mg%dLAST- ÃâÓ÷Ú³Q52
ALT- ÃâÓ÷Ú³Q52
2mg%dLCre- 1#

1(Ô(DºãQ@ÁÓ!!!
kshb$qËQÁæ14-~,'14-~,P>ß«ëA\K9[M=PR%IÁ-P¦9-Q÷
^»LC[(P~QÜ®^CTKCGC@M^.QÚ"(DºãQ@^Ã·C[!9D\;1JLWCGAO9Û¹R"ËQÁ^B"ËQÁÓ^CGBG@M^.BK;Y"
(DºãQ@^Ã·C[!
2(FOLFOX Q@ÁÓ:XS2E~¸Q(DºãQ@QËQÁÓ'<4(!!!!!!!
3# !'4&+%/5(,)0

u
v
w
x
y
z
{
|

4­¤ßUGRµø¤ . 2"
500%mm3UGR1"200mm33­Õ7. 5#
0,104%mm
T.Bil- 2#
5mg%dLAST'GOT( - ÃâÓ÷Ú³Q52
ALT'GPT( - ÃâÓ÷Ú³Q52
5mg%dLCre- 1#ä^£]E[37/~ÚQ5/<O9
ô&<%I=1M6öC[GÈÙ^.VO9#!)54&(,287%67
Seldinger @^L9K"©`g$gqÿP"çPïBK_pig`tÝj$d^(D,P%I
C[!n_as`g$gq^L9KL=[H?åóÿP'ÖO>MW§ÄrlqXZWB×L(F¼^%IC[!Ï¢QÐPm_thR"­O<üðC['2&53(Lê¼<ØÌC[þ$("8[9R"1
V ^CTKÀLBGÉ#MC[!
õ0(DR spare B"ØONQ
;YQN­<í½BGÛ¹R"!¡­O?RÃ·BKWX9!

N­<¯J;IGÛ¹R"eoftONQ blandTAE QûR¥JC[!UG"j$d^ 1V ÀL´P­)<Ò²BGÛ¹R"ÎËQ6öL blandTAE QûR¥JC[!
$!/+08%3.*1'<5(
3$ .*2-)0

u
v
w
y
z

Êb$c%IÁHý-XZ14-EULP%I^ÁL=O;IGÛ¹
(ùºãQ@Qrlq+1XZW"AYO[±R<;MMOIGÛ¹
Grade4Q:­+à<5²BGÛ¹
9°Í<ÆABGÛ¹FQî"ô&Â'<øÅ^;MM6öBGÛ¹

9D\;P&BGÛ¹"Ç°ËQ^øÅC[!

8 Y ¸ P I 3 Q M

21%"40.-&*),3.-6(/2'8+=³J"ü@}¬ÛP:¯¡I2ãrHRU½O"O=:JèIMIHRU¸Pï±LE8³¸PFGU!®X³¸PI«½`%a¯7S1¾LEF=";VSIïJs|I¦FHC4D©#®X¥5!
-(¼V1~
1~27J"`%a>H65 CT HRT1~X¥5!ãrXW?UÆÌÀ

¶JÖ¶"CT LAJ MRI ûI©X¥5!âÓí"3U4JQÄÓíHRUãrIHAX1~=9¨>U!
.(ÞÔÌë"¹èÆÌÞÔ}P:ïJ.¾H-sÉ"ü@}¬ÛP:ïJ-`%aH«ó-"©#®X¥5!
`%a8.¾sÉHy<VUÊ§EO"«ó.¾H-I1~X¥5!
ÞÔÌë$PS'ECOG("é¿'é¿IM-(¹èÆÌ 'CTCAEv4.0I Short Name(!Å}$rÏ"U÷"ÎL3Ð"|N"8."$?z'Ó®Á(+¢¤"$?z'%&ÆÌ(+¢¤!Ü$2/+0I£ïÃX)5Ü'Üà3C(
2/+0I£ïÃX)5Ü'QÄõH!(+)>KD*
2,+.I£ïÃX)5Ü+)>KD*!Ò$ÒÈ$vüØ"ÒÈ$Ø!ÞÔÆÌ$,S"("'2/sÉI£ïÃG=(!Zon]%&Dx$Zon]%*{!-4&-4$-Ñ"Íßñî"ìE!&#Éý$&äz
!@Iè/(QÄ©
s|I¦FHC4D.¾H-sÉ©>U!G6"·`%aùK¯ÿIÝÿLAJúÿùKÝ
J0ÕF>U!þH"Grade0I'ÃLAJ£ïÃ8!NSVAÊ§HJ"@Iµæ8!E9UR5Hº°>U!
w©$'×"£ï×"Â+×"hl_pfq
wÙ}$Zngjq"áfmnfq"AST"ALT"ALP"LDH"^oZbeq"dcm[k"\m[k"CRP¼Vi%\%$CEA'0¾H-($#"75.-6(,3!/2!8+19
òÚFJ"®'³¸PI«½`%a¯7S1¾LE(½O¡IX<="«½øTÆRIøTÿ7S-#LEF>U!ÆR8²;=AÊ§"@I¶öXOBDòÚX½OF>U!2Iã
r8!NSVQÄ³X½O=AÆRO"@VsIMI'H´ÇP/»<(HRTQÄ³Xï±=AÆRO"òÚIêÇFGU!
-(â©"¹èÆÌ"QÄ©
åF=DòÚð©F=DJô=G4!
.(ª(Ë9"J¡Ë92IãrsIMIEQÄ³Xï±=AÆRH=DJ"ãrIHA'ãr!ÿ"5t(Xð©>U!ÞÆRH=D"¡¸PIHA'G­B"¸P¯ÿ("²;ÿLAJ«½Ùç!ÿ"²;REJ²uXð©>U!

Â×ßæpFÖ:UYf`^Zi&³Äa%]éÿÊ*ûGØjÎ¦22%%"<-2!(32'9)(32'9)-(%y§¼Gã%y§¼DH"©*PµÜF9B
Go¿O

8VU"1SQUK97E2nÃ9E2Þ',¹Û

M("»À"¬C1T"©*PµÜDGqvX#WE2!

%y§¼GôsH"%y§¼â´ v4.0 êý$ JCOG&JSCO ï'CTCAEv4.0(X'2B grading:U!ý¦CH"CTCAEv4.0 FRU grading C"¦ç.ËFñJB Grade 6-m½kr9=O
GX%y§¼D:U!)-/#.#¦4RI

ÝGDôs*Cã9=ªÔ|»ÀD,¹

"F@2BH"%y§¼5ð5FWS;"[%\þGk Grade K=HkÛXú:U!
<GÔG§¼F@2BH"Grade.m½G%y§¼GLú:U!
<-2'9)-(!Ñk Time to progression
ç.êX¡êD9"Ñk6¶F{ë8V=ê"KCGD:U!ý"CG)Ñk*DH)w
Ð½GÑk*DwÐÁÚFRSE2),¹äÑk'Clinical PD(*G)­X

M!wÐÁÚFA2BÑkDîÚ9=¾H<GwÐX?=êXÑkêD9",¹äÑkG¾H,¹äîÚêXÑkêD:U!Ñk6{ë8VE5?=­HÕ>ÈTD:U!
.(ÌÆÓ Overall survival
bh_[%g©*x£ê5S"1SQUqFRU¥üêKCG!ÆÓ-CH°ÆÓ{ëêX¨?BÕ>ÈTD:U!áÇöì-CHáÇöìDEUmËCÆÓ6{ë8VB2=êXO?BÕ>ÈTD:U!
/(Í} Response rateÒãuìõùX%:Ubh_[%gFå9=Ö¼±ÙG3>"©*F42B)-/#.#0 +Ï
v*6 CR"PR G2;V5C1U­G}XÍ(D:U!RECIST criteria ver 1.1 D mRECISTX¢':U!
.=/1'-*75vîãý¦F42B"®=UvîãH RECISTver 1.1 4RI Modified RECIST X'2U!
86:;'-*75+0#Modified RECIS&!RECISTver 1.1 ,4$!CR'complete response($~ÌÍ:JBGóäõùGº«!
!PR'partial response($÷øÍóäõùGà/6c%\eYià/Fñ9/,+m½¸!
!PD'progressive disease($ÂóäõùGà/6"<VKCGO?DO·82à/Fñ9B.,+m½Ñt'íX
!SD'stable disease($lãPR Fzè:U¯0²·P PD Fzè:U¯0Ñ×XëNE2!
!NE'not evaluable($ôsöìòóäõùGvîã´'Modified RECIST"RECISTver 1.1 â(!CR'complete response($~ÌÍ:JBGòóäõù6º«5@"¯0d%Z%'AFP"PIVKAII(6Å¿r'¤É´(!
!IR&SD'incomplete response&stable disease($ö~ÌÍ&lãM(!

= a É E Q 8 Y V

23/JÚQ*+û-1QÁï<J'UHRÌKv&e&=ÆæãÜõÚ²`:]!
!PD(progressive disease)$à·*+û-1Q7[<Ní!NE(not evaluable)$,.%[<QA:L­½=·:N9Û¹"UHR CR"IR'SD"PD 9G^MX(úL>N9Û¹)+#/0.'
5$7¬OGAQÖ#`Í@"×IýJ`ÃEH!°¿×IÏä÷L8]!
*&

5®¦LR"D@ð'òø¡ü×I`ñÙMEK"FOLFOX E3/?bxpmez>Ñâr&j`?9H!6¾çE3(DEBTACE)Qéâ`­ØF]BM`8ûME"»³Qà·òø¡ü
OñF]Ý¤ÉE3Q¢)MN]®¦MEK9>H9M¶:K9]!§$"òø¡üåÔ³Q;³RèEK9]!E<EN=["D@ð'×IQ;³RèEK9]MR±9"9!%R"2eÓÚQòø¡üåÔIQ­ÿ<["ÎÒ£E3`·IKX"7[<N;³è´R#W[^N9BM`2ºEK>H!D[N];³èQHWORÝ¤ÉE3Q'=4U^]!§$"0LR"òø¡üOñF]bxpmez

Þr&j(drug eluting bead irinotecan$DEBIRI)`Â?EH!6

¾çE3(TACE)òø¡Qéâ"9´â=ðá2ºD^K9]0)+7)!Martin [1)R"åÔ.%N
ü=8]ÊOñE"FOLFOX*uqgjvsQþ<M"DEBIRI `/?F]ó~ìÇ¯`Æ·E"éâM¸9ê´B`2ºEK9]!ÉEªî£O¼R#WG(/.vs.7 cycles)"fy&o1'2Q9ÈÙOX9R#WN<IH(32vs.24-)!Response rate R DEBIRI ¨L9

OFµL8\(0{¬$56vs.32- p,.#.0"2{¬$73vs.5.- p,.#.1)"lczim&hzfOZ\åÔ%MNIH¹
R"DEBIRI ¨13-"FOLFOX*uqgjvs¨/4-M"9O DEBIRI ¨Lð?#W[^H(p,.#.3)!

ÚQ&©<["Ú¥QHÕÇ¯`CEH!°¿×IÏä÷L8\"ë£O7IQýJM·9H9M¶:K9]!5®¦OZ\éâ=­ØD^^S"ó}ìÇ¯`Æ·EK9?;úMEK9]!5®¦Qéâ"9´â=Ø7D^^Sòø¡üÉEO;9KÝHNÉEdtgwzON\Y?%âX8]MÄ_^]!
! % $ "
»"D@ð'òø¡üOñF]Ý¤ÉEMEK"FOLFOX E3/?bxpmez>Ñâr&j`?9H!6¾çE3(DEBTACE)Qó|ìÇ¯`«EýJ`ÃEK9]!°¿"5ÉE3Réâ`­ØFT?ªî÷L8]!»³"D[N]n&kQöä`ÐPK9?ÓïL8]!
-,5HÕ®¦OCAù>"CÅù9H=aÏûÉE®¦ÀôQ=OËßEÚAUF!
1(/)Hokuto D, Nomi T, Yamato I, et al : The prognosis of liver resection for patients with four or morecolorectal liver metastases has not improved in the era of modern chemotherapy. J Surg Oncol 114(8)$737+43"0./4#0)Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy forhepatic metastases from colorectal cancer : a randomized trial of efficacy, quality of life, and mo-GCLNA@O?3K256<:97=SFH;$8@PRDITQ4M>JEB

24

lecular markers%CALGB 9481&. J Clin Oncol 20 ; 24%9&#)+1-',(+!*((."+&Martin RC 2nd, Scoggins CR, Schreeder M, et al. Randomized controlled trial of irinotecan drug
eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liverlimited metastasis. Cancer 15 ; 121%20&#+.,1'-0!*()-",&Martin RC, Joshi J, Robbins K, et al. Hepatic intraarterial injection of drugeluting bead, irinotecan%DEBIRI&in unresectable colorectal liver metastases refractory to systemic chemotherapy :results of multiinstitutional study. Ann Surg Oncol 18%1&#)1*'0!*()) Jan"-&Fiorentini G, Aliberti C, Tilli M, et al. Intraarterial infusion of irinotecanloaded drugeluting
beads%DEBIRI&versus intravenous therapy%FOLFIRI&for hepatic metastases from colorectal
cancer : final results of a phase III study. Anticancer Res 32%4&#)+0/'1-!*()*".&Aliberti C, Fiorentini G, Muzzio PC, et al. Transarterial chemoembolization of metastatic colorectal carcinoma to the liver adopting DC Bead®, drugeluting bead loaded with irinotecan : resultsof a phase II clinical study. Anticancer Res 31%12&#,-0)'/!*())"/&Czejka M, Kiss A, Koessner C, et al. Metabolic activation of irinotecan during intraarterial chemotherapy of metastatic colorectal cancer. Anticancer Res 31%10&#+-/+'0!*())"
0&Eichler K, Zangos S, Mack MG, et al. First human study in treatment of unresectable liver metastases from colorectal cancer with irinotecanloaded beads%DEBIRI&. Int J Oncol 41%4&#)*)+'*(!*()*"
1&Bhutiani N, Akinwande O, Martin RC 2nd. Efficacy and Toxicity of Hepatic IntraArterial Drug
Eluting%Irinotecan&Bead%DEBIRI&Therapy in IrinotecanRefractory Unresectable Colorectal
Liver Metastases. World J Surg 40%5&#))/0'1(!*()."

: g ê  R 4 _ Z

25

8=7034'#$) microbiome (>@;1:!
95.+,/"-"2<*?6%&j% !ã*"¥â Õ*"h¹ Ñ5*"9 0*"³[ 4Ò*"» ä*"¹a Z*"j% öw*&% Fusobacterium SñQÐ×gQ7ECc microbiome RóM"çõuRÌÁM4c!Âi"Fusobacterium :O
X²C(M6&C(QmVI<7EA"OX²Rk²#,ûU°Cc?N:Ú@dG!Û¥")d².-/ÿ¡R Fusobacterium nucleatum R DNA f\hyj PCR QLF\A")d²7Êtf5G Agilent Miro Array Q`cKEGG pathway¤8fØJG!)d²xMS"p²x`b]QFusobacterium nucleatumRkÍ:ÙSM4JG!
Fusobacterium nucleatum 2ÄS"2ÄQmVLQ²f]7H·¯:Q<"A7HQ°AL]cRÈ£:e
adG!Microarray |%yR KEGG pathway ¤8MS Cytokinecytokine receptor interaction :Ý$R term NAL½>ad"Fusobacterium nucleatum 2ÿ¡MS CXCL8 N CCL20 PORqnj:ÙkÍAL5G!Fusobacterium
nucleatum 2¡SQÏvM4b"Fusobacterium nucleatum :)d²R-_#,ûQ°AL5cNÖ7adc!
FR2bQ¶CcnxNAL"Fusobacterium nucleatum ¬=Q`c cytokine upRª2¡:ëÜ@dG!

# ! $ "
òú"¡©"î>"¡©î>POf±[÷©]êRkPQ]°eaD")d²R
ÏSHQvM4c,(-(!FRG\"µBË¼ºT

ýË¼Q`b"zås]QNt@dc¨+]PêR¦k:á@dL5c!²Q8=c microbiome S²ê#²¡©R target NALp&Q
M4c!@aQ"«ïÏN°£Cc microbiome fc\Cc?NS"woQBGê.Ç\QI"YG"FR~¡fs]NAGê:¦k@dGßQS"K#«ï@}R%n%NAL5
adc?N:·L@dc!

R)d²R2+)$:¤{$n²M4cRQKA"$f<\L8b"

N

Q°CcµBË¼#

ýË¼S"h:U*NPJL%~AL5<r:4c!

|MS?²:0+)

|MSC(©]zopk~:O;<Pc!FRG\")d¤{$n²

microbiome NS/JQ7HCcq7yÄNFR`å8`TNðª2RD"M4c.(!/JQ85L
S",.WR}Þ:,.+WRÞÁÞN¾HAL8b"YG"-R}`å:"/++&1++RÞÁ`å"5e_c microbiome N¾HAL5c!microbiome S"Âi"o"ÿ2Xì«"phs%2æ2®ì«PO$Pì«NR°£:Ú@d"Vf÷\L5c;R2RÙ5zM4c!
I<R­¿å"`]å"mvl{izoPåQ`JLY:#~Ó@d"FR/RfPÞÁ'M:Æ3@dc!microbiome RI2S"JRx"Î/¯"i¢")èPOQ`JL]~¡A"YGé¯]Q]~¡Cc!Î/¯RÞÁÔ3RI2SÀ<WOO;5:"Fd:øñQcB`6PàfºXC'tÍÅí(N56?N]z9JL5c!KYb"microbiome SÏ^]Q~¡@E6c]RM
4b"ì«êRy%rz}NAL];e\LM4c!
Fusobacterium nucleatum 'É¸2Rp2Á(SñQÐ×gQ7ECcXgÞÁRKM4c!
l]QSçõuRÌÁNALTadL5c:"Âi"Fusobacterium nucleatum :OX²Rk^_Q°AL5c?N:Ú@dL5c!OX²

ýÊJf5GË¼MS"OX²ÿ¡R/-)M Fuso-

bacterium G:Êù@d"jot{j}v\2'MSI(PORzå&Q°£AL5cNÚ@
dL5c!YG"OX²C(UR Fusobacterium nucleatum DNA :I5ÿ¡Sô¦U3Þ1:ü
*ÃO©O©7¢©Ë¼x þ¡´§¢©

26ÊýÆQ?B[ microbiome R+4ìÔ%Îsbdz'e'õ],¸EL

P<CN3*"æéÚÌçR Fusobacterium nucleatum DNA 9Aã<Ç;S.®û8M;[CN4*"æéÚÌçR Fusobacterium nucleatum DNA 9A*é@Y:Ë§éQ@BL linearly Q«ÄF[CN5*"POA)Y@QPKL<[!DYQS"£ô"Fusobacterium nucleatum Aæé³&R Toll 1¿0ä)TLR4*Nzbg RNA)miRNA18a N miRNA4802*]êÖE"d'qu_j']ÞÐF
[CNQXKL"¯A^´)dfh}w|n;[<S4+u~dc|i~*QX[`yq'ik)³&º*]ÛF[CNA#²D\L<[6*!
E@E"Fusobacterium nucleatum AâRÆRÚÌóQáµF[R@"ORX=QQ¢]/>[R@û)PýþAã<!'ª¡R,ìS"ÆQ?B[ Fusobacterium nucleatum Ráµ]ÔF[CN"ÍòQ?B[ Fusobacterium nucleatum N.®NR¥])Y@QF[CNM;[!
#$#Íò""æé"?"³&R1/;Rx~z}­ët|ua"(vogRý?
XTøýÚÌXZ DNA ]èÁEJ!DNA èÁQS"QIAamp DNA FFPE Tissue Kit)Qiagen"
Valencia"CA"USA*]¶2EJ!»Q"}`~mb{ PCR %]2<LH\I\RÚÌóR Fusobacterium nucleatum R DNA 9]ßëEJ!Reference NELS human gene SLCO2A1 ]¶2E"
w|bz'SRN?ZM;[!

F. nucleatum forward primer, 5TGGTGTCATTCTTCCAAAAATATCA3 ;F. nucleatum reverse primer, 5AGATCAAGAAGGACAAGTTGCTGAA3 ;F. nucleatum FAM probe, 5ACTTTAACTCTACCATGTTCA3 ;SLCO2A1 forward primer, 5ATCCCCAAAGCACCTGGTTT3 ;SLCO2A1 reverse primer, 5AGAGGCCAAGATAGTCCTGGTAA3 ;SLCO2A1 VIC probe, 5CCATCCATGTCCTCATCTC3#1//4ô3¨@Y1/02ô5¨UMQ¤'æýüàúQLìÕÃA¹°D\JÍò214;]åÉNELÚÌóR Fusobacterium nucleatum R DNA ]ßëE":Åú5ì·NR<]©ÈEJ!2//;)81.*A=ÿÊ÷"01;)2#
6.*AØ"02;)3#/.*AâRÚÌ¦M;
KJ!006;QåELÂÙ7%A¹°D\L?Z"62;A7%)ikw|n"5FU,r
lmfl~*"33;A$¼×7%M;KJ!
#zbg`bp'mR Kyoto Encyclopedia of Genes and Genomes)KEGG*pathway Ô]°<"ÍòR Fusobacterium

nucleatum 3ÒÇ;Q?B[!ðî·]ñëEJ!Íò0/;RÓ©hw~@Y RNeasy Mini Kit)Qiagen*]2<L Total RNA ]èÁEJ!zbg`bÔS"
SurePrint G3 Human GE Microarray 8x60K Ver. 2.0)Agilent Technologies*]2<L¹°EJ!
!

"

#Íò"?XTæéÚÌQ?B[ Fusobacterium

nucleatum R©Á6SH\I\1/.)3(1/;*"0/.)1(1/;*"34.)8(1/;*M;KJ!øýMS"ÍòNæé@YS Fusobacterium
nucleatum AH\I\4.)0;*"3/.)7;*©ÁD\JA"Røý@YS©ÁD\P@
KJ!Ý?XT?ÝMSý$øýR<G\@YW Fusobacterium nucleatum S0;W©
ÁD\P@KJ)ù0*!
ÍòQ?<L"±6Q Fusobacterium nucleatum A©ÁD\JJV"ÍòQELÀíìQ©
ï]ÐV[CNNEJ!ÍòRÚÌRçM"Fusobacterium nucleatum R DNA S¾>RÏýX
ZW½QùÜýQ?<L©ÁD\J!
5/;RÍòÇ;Q?<L"ýMR Fusobacterium nucleatumRõ¬SøýNöEL-Q±@KJ)9-/#/10&Ñ0*!

? S n  J < N L

27>! 6.10*$%, Fusobacterium nucleatum =2A
&(
wc
\c
 c
akc
c

Fusobacterium nucleatum&3
1&3
0.&2%0.'/.&0%0.'23&7%0.'..-

3&/%0.'.2.&6%0.'..-

9! Fusobacterium nucleatum +8<0:7(3=2&'#,

X#wc10352&01-'F Fusobacterium nucleatum J DNA ?hqAQD!cI=@P Fusobacterium nucleatum iK.#
1.*/.(1(06/7*/.(1&` 01#/*/.(1'F<ED!
Fusobacterium nucleatum iKUV$T&;+.#./4'":]m&9,.#./'"8]m&9+.#.17'
GbRMD?"z""performance status"d_"^p"}vg"oJfl"r|nJGJbKMH>ED&0'!
>" Fusobacterium nucleatum =2)B5?@/;-4
6*25%/#'-+7!

)80 F. nucleatum
$,
4,

103
43#
7)7#
0

03/
43#
4)7#
3

52
44#
5)6#
.

z
sz

065
16

00/
1.

44
6

<O
HB

05/
32

0/.
2/

4/
/1

<O
HB

052
3/

0/.
2/

42
/.

<O
HB
o[
(euw
e(w
}vg
uc
{c
CJ
xj
W
X
Y
Z
r|n
<O
HB

001
/.0

/53
54

26
04

32
05/

24
0.3

6
44

1..
/0
/1

01.
/.
//

5.
0
0

/33
20
//6
/.

/1/
10
60
4

02
/.
14
2

//5
0.6

61
/46

12
2.

ty

z

d_

".
.#
30
/#
.

.#
64

^p

~t

.#
50

.#
26

.#
/4

.#
42

./4
.#

.#
.31

¢Ä

28

y

N?AV microbiome OÉÐ¶}ª$¦cZ[h&\&~¿XÊDJ

Fusobacterium nucleatum Ï¨P"v¨NÀQJ¼r¶©®@ËqNÃÔK;HG)log
rank :,0#039"³ÅÕb_&aÀ 2#
01%95/¥Ñ 1#
22+3#23":,0#0068%§2*!°ÅÕ}ªN?<JT"Fusobacterium nucleatum @½ÓDGÌuK;UBL@¾CWG)°ÅÕb_&aÀ 1#78%95/¥Ñ 1#
06+2#
94":,0#031*!SG"Fusobacterium nucleatum @ÌNÍ>VwP"¯OÖÂÒ¶uOwXAM<BL@¾CWG)all p for interaction.
0#
09*
!

癌特異的生存率

生存率

Number at risk
Years

0

1

2

3

4

F. nucleatum ()

251

191

156

126

85

F. nucleatum (+)

74

49

36

31

19

手術からの期間（年）+! Fusobacterium nucleatum 1,*3'0).2&#(

o#KEGG pathway }ªKP"'cytokinecytokine receptor interaction.(NSWVs·@ Fusobacterium nucleatum Ï¨KTÅ¹DJ<G)false discovery rate-0#
001"fold enrichment.1#95%§3*!FO´KT^i\ZnOtIK;V CCL20 O¿Õ@­{DJ<G)Á3*!FB
K"²P"Fusobacterium nucleatum @^i\Zn CCL20 O¨yX|DJ¤ºOp¨¸»NÍEVL<=z«XGJ"CCL20 OÈx¬£X<¡EVBLLDG!Èx¬£P"glhknµdjeYnÆÇfm`]XÎ<J<"±P rabbit monoclonal antibody CCL20)ab9829 ;Abcam, Cambridge, UK*XÎDG!Fusobacterium nucleatum Ï¨KËqN CCL20 ¿Õ@ËqN­{DJ<VBL@¾CW)§4*"Fusobacterium nucleatum @ CCL O¿NwXR
DJ<VBL@CWG!

)(10(#&'%!$" pathway+" Fusobacterium nucleatum 1,3&/-$% KEGG pathway

7 O m  B 2 H E

29

C# 45326/>,0A. CCL"!';0D?)+%**Fold Change

Locus linK ID

Gene symbol

Gene name

)*#
0
)*#
.
0#
0
0#
,
,#
)
+#
/
*#
/
*#
+
*#
*
*#
*
*#
)

.+.,
-,/+
+-/.
)(+,,
-/((/
*1*)
)*+/
-))1*
*1*(
*1)1
.+-*

chemokine&CC motif'ligand 20
CCL20
PPBP
&CXCL7' proplatelet basic protein&chemokine&CXC motif'ligand 7'
CXCL8&IL8' chemokine&CXC motif'ligand 8
CCL26
chemokine&CC motif'ligand 26
ACKR3
atypical chemokine receptor 3
CXCL3
chemokine&CXC motif'ligand 3
CCR8chemokine&CC motif'receptor 8
CKLF
chemokinelike factor
CXCL2
chemokine&CXC motif'ligand 2
CXCL1
chemokine&CXC motif'ligand 1
CCL5
chemokine&CC motif'ligand 5

CCL20 !"CCL20 #"CCL20 score : Area(04)Intensity(03)=$ <@8.&(1 CCL20B:- Fusobacterium nucleatum /79"!

9MD>"$@coA53="Fusobacterium nucleatum ?g?Bb7e:M=3L7"^;<dC6M=3@3!JC")((([tB|~cNaw;"Fusobacterium nucleatum DNA
ZVY7h3q>C\Ag>2L9?Ni;=3L-'!^>C"Fusobacterium nucleatum?|~cBgCb;@3?34iFkf:ML!9MJd`Bx]C"Fusobacterium nucleatum
epB]3G"aw{sB]3AILFB6F;M@3!l}C"J?Bn> Fusobacterium
nucleatum ZVYNep;"Fusobacterium nucleatum vucqC\Ag>2L9?N
J6A;<!Fusobacterium nucleatum 7ucA58LgyUPQX%R%?;=>2L_
v72K"jg"zBSW%TN3<er7>2L!

·à´M<@Z microbiome NéóÑÃ%»m`ao(b(Ü\ê¬CI

30

Fusobacterium nucleatum >N¼ÓM|\RDqblgpMH:IO"ï'Lj(h®B[I:
Z!Fusobacterium nucleatum >"¯XNÝèMË©DZ FadA)Fusobacterium adhesin A*\

CI²÷§äN Ecadherin M¢C"ÐÄÑMwcatenin \ÀDZAKJÏ²÷Á\Ê¼DZA
K>ã£B[I:Z6*!SF"ÍÏÆ¹ÎN Fusobacterium nucleatum NË©õK8§ä)CD3 ñÀ§ä*¾MßNö>9Y"³±ç}Nò¿\CIÍÏN¼ÓMîCI:ZAKUæX=MB[I:Z !¤No`cu^t`ÃJO"Fusobacterium nucleatum ñÀº×Æ¹JO"µÀe`k2*b`vMöDZ{öNyÔ«>¦UâÖCI:ZAK>æX=MLGF!e`kb`vNÎJUÙM
CCL20 V CXCL7 K:GFdrb`vNyÔ«Nõ>ÉCI<Y"A[X>NxÀÕØMîCI:ZÛÀ>®¥B[Z!
! $ # "
¤NMWGI"¡Ú¸©J9Z Fusobacterium nucleatum >drb`v\

CI"º×

NÜz$¼ÓMîCI:ZÛÀ>®¥B[SF!ÏÚ§ÈOnum`ai_cf)Probiotics&½
ÌMí~LÏÚ§ÈLXQMA[X\TºÞ$ÂÞ*Vntm`ai_cf)Prebiotics&ÏÚ§ÈNmsvf\ÅDZªð>9Zá°*MWYÒÑMâBEZAK>J?Z!¤NM<:I"º×¼ÓM<@Z Fusobacterium nucleatum Në>WY¶§MæB[[P">]­ôN»FLÇìM>ZÛÀ>9ZK;I:Z!

åÁO"+Clinical Cancer Research,M¨B[F7*!
&%/*Baba Y, Yoshida N, Shigaki H, et al. Prognostic Impact of Postoperative Complications in 502 Patients With Surgically Resected Esophageal Squamous Cell Carcinoma : A Retrospective Singleinstitution Study. Ann Surg 264%1.3-//"0./4#
0*Baba Y, Watanabe M, Yoshida N, et al. Radiofrequency ablation for pulmonary metastases fromgastrointestinal cancers. Ann Thorac Cardiovasc Surg 20%77-/.3"0./2#
1*Baba Y, Iwatsuki Y, Yoshida N, et al. Review of the gut microbiome and esophageal Cancer :Pathogenesis and potential clinical implications. Annals of Gastroenterological Surgery 7%0./5#
2*Mima K, Sukawa Y, Nishihara R, et al. Fusobacterium nucleatum and T Cells in Colorectal Carcinoma. JAMA Oncol 1%431-4/"0./3#
3*Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue andpatient prognosis. Gut 65%/751-6."0./4#
4*Mima K, Cao Y, Chan AT, et al. Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location. Clin Transl Gastroenterol 7%e0.."0./4#
5*Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell 170%326-41 e/4"0./5#
6*Rubinstein MR, Wang X, Liu W, et al. Fusobacterium nucleatum promotes colorectal carcinogenesis
by modulating Ecadherin//betacatenin signaling via its FadA adhesin. Cell Host Microbe 14%/73-0.4"0./1#
7*Yamamura K, Baba Y, Nakagawa S, et al. Human microbiome Fusobacterium nucleatum in
Esophageal Cancer Tissue Is Associated with Prognosis. Clin Cancer Res%0./4#

$"#!*&(')+%! SÅNE+)ý4+*c³×EMD:!

"

?

¹

400¼

.

15

4

+

400¼

. 105

¿Ò$Õ%

105}ü)¿ÒTvqhz*

>+

10~

¨Trmj{cC¸>SÎ"Ü;>¤}T÷>¼"¡æ=QL=:),>Q*c>:",8ARûóTØR<É?D:!15R40¼.40ªOE"ªcN?`K@9@Mtw{pegpEMD:!XJ"CD-ROM"DVD-ROM øRo&nc0ãEJ[Sc"¸>Ã"msp7c8SÎ"ÈR<à_D:!

#=&SÊ&7)+*Tç+¼"7"#7TË+¼N±D:!

$Ö¼T·>Ö¼c>:"õB«ë~T CGS ë~N m"cm"mm"cm2"ml"l"dl"kg"g"mg QP
OEMD:!

% ¿ÒTÂ´}ÎSç?DNÞ8N9`BO"+¼\<c­G`Ï®Tpy&k{iu&r&c=@JÎR8EMD:!
&¨TáOEM/:JEXHd!¿Ò"ÕQPN/c?G`[SRTIS¹8EMD:!

' +T4+ïR>DaJ[SSYc9AMD:!4+ïS>¢ÇRT$­c(EMD:!
( +SÉ?1T½S];RùEMD:!
>+"ðÁ7T3ÔXNE"Ia}ÎT+ä,+et al,OEMD:!
¯+S±¾T Index Medicus Ç±RÅFMD:!
µ»SÏ®/>$­*ðÁ7%E+é7"µ»7"Ö"-Ö)ÙDþ­*ëª4SÏ®/>$­*ðÁ7%E+é7"É7).Á7*"""-"!ªÇ7"!ªî")ÙDþ
­*C

1*ô¥Fí"£§ Ì"ò

9"ä%S@2#O@2 7)12*%108-114"1870#

2*6ü'"ñêÝÿ"¶²

Ñ%°3SßÓì2#gfxl=^°3W)*)

Ð.*"è2""308'327"O@2À"ö"1872#

3*Umezawa H, Aoyagi T, Suda H, et al : Bestatin, an inhibitor of aminopepitidase B, produced by Actinomycetes. J. Antibiotics 29 :86-88"1865#)+úT"TFZRNTFX_"<b_RNV!

*

E+T?¹-TFZR-)åÍ-12-×Ú*-©|-<b_R-+-%-ÕSÛ8-ÕSÆR
¨c¦×EMD:!Õ<]U%RT+ïRÄ`Æ$R$­c(EMD:!

+¬:T½S];Q­c>:XG!
-#

,

((1#

((1*

((a

¨RT%ºc(E"%é"ðÁ7"Çâ"7" ¨5Ö"Õ%óÖc8EMD:!

#-&%()'#.!,$+*"%+*%®÷Ã60#U¶B$Bä$Ì

}0#îAÏ¶Bô:?BaO$#%C$Èö

6³#Óð¶B2Bä$³É

1ý#1¼b,-.0/"$>ÎÇ0#É¶B2Bä$@Ò#q&óf<Þ8$Eh¥#ÌP¶B2?BaO$oc¸üL#¬þ¶B2Bä$Ú 4à#ÌPÊ&VrÞ8$¨ò¥#Ë¶B2Bä$÷ðJNý#U¶B2Bä$ÍN)à#Ãv¶B2Bä$é% ¼Ô#ÌA¶B2Bä$ãÆ#¶u¶B2Bä$

LÉ

#PÊ¶B2Bä$û3®÷Ã60#U¶B$Bä$

3²

üà#PÊ¶B2Bä$#&C$A/ó·x0 #Ìî¶B2Bä$f@¤#Ä¶B2Bä$~É[x#Z×¶B2Bä$À¨Û#îAÏ¶B2Bä$×l»#U¶B§´íg2BaO$

%+*&

y
úÉ
Ë

ØI#¶uá&¤Þ.0/"$ì#óf<¶B2Bä$ºà#ÌP¶B2Bä$#Ìî¶Bm{TÞaO$Îð õ»#1¼2?¶B$t­¢»#îAÏ¶B2Bä$5 ¶#Ìî¶Bm{TÞaO$

É

ÁK#ÌPÊ&VrÞ8$xi

ùà#o¼2?¶B$¾É\6#U¶B2Bä$©7

Nø#]2K¶B2Bä$#'C$ö²40#;y¶B2Bä$X÷Ü#¶æ2?¶B$¡e

pÜ#y#2?¶B$oN|ñ#ÌP¶B2Bä$M

ãÜ#Ìî¶Bm{TÞaO$ÿ,90#ÐË¶B2Bä$¨ç

Ç0#Ìî¶B2Bä$÷²

7à#q&Þ8U,-.0/"$Îe¶Û#¶u¶B2Bä$¯É

n#Wð¶B2Bä$xQ

#N'è¶B2Bä$¹Ñ

#wï2?¶B$%+*'yðxHà#U¶B§´íg2BaO$
%+*(

¶¨

p#U¶B2Bä$÷à#ÌPÊ&VrÞ8$#(C$ªÉ

Yx#;y¶B2Bä$

6ð5dL#¿Ö¶B.2B^$

Es

3ß#q&,-.0/"aO$

!É
e

%+*)

ü#îAÏ¶B2Bä$µD#q&Þ8U,-.0/"$¯yF#Ä¶B2Bä$yÉ

6¥#óf<¶B2Bä$`y#)C$S#kË¶BeÙêÕ2BaO$Â[°#U¶B2Bä$o_¦#Wð¶B2Bä$ÅÚ(#Ga!G=B+ë.0/"$å¨*#1Ý¶B2Bä$!

»#ÌP¶B2?BaO$£à#]2K¶B2Bä$î²jÜ#¶u¶B2Bäâ±GaO«$

¥½#

-

"#zR2?¶B$@2?¶B$

&+*'"0!+$8,-.0/#%$'M%áÛ

&+*(

º*

q

|ÿ$ÜÕJ3Jü%

qá



åá

±:$ÕÕJòÅþõnY­%#È*Ù$^o8,-.0/#nY­%²Ø

GÅ$äZâ8dõ7%

sÀ

¦5$8õ73;.0/#%

Váu¾$ö²3FÕJ%Õ1:$-rBÕJ3Jü%Þ?$äZÕJ3Jü%!1

mí$On!OCJ;%.0/#%¡1 [5$äZÕJ3FJnY­%0Ó

pQ$b¥ÕJÅÔ's3JnY­%W"áÞ>$hCUªÕJ3Jü%e*=.$)3FÕJ%4 "¹$äZâ8dõ7%¢cÏ?$éãÕJ3Jü%áÛ¹Ù$äZÕJ@4òÅþnY­%áÛ

iÄ$NÆ3FÕJ%ÆáT÷$`SÕJ3Jü%ë1 ¾$ZâÕJ3Jü%,$vãÕJqñ$î3JnY­%$aÖÕJ3Jü%

3$ÜÕJ3Jü%\* µ$hCUªÕJ3Jü%8Åø÷$äZ®3FÕJ´CRõ.0/#%öA 7í$ÕÕJ3JüûÒOnYÉ%

Îá

E?$Ý

\

Õ»

xí$AÕJ3Jü%°±÷$Ë5o,-.0/#%§¿$åáJ>"l;ÅÕJ3Jü%w$¬àæÕJ3Jü%

ÕJ3Jü%¯³¹ô$éãÕJ}ÐFJnY.0/#%Eå?$ÕÕJòÅþõnY­%aÖ{ì$ºKÕJ3Jü%*«5$2Úo,-.0/#%å¤$2Úo,-.0/#%=0+?$ä(ÕJy_õnY­%~*$äZâ8dõ7%èÞ$vãÕJqñ$î3JnY­%ÄAß$Õú8Â¾õ.0/#%²* f$ÕÕJ3Jü%X""$(IçÕJ3Jü%t&$Ë5ÕJ3JüðOnYÉ%

Vá

BH$ºKÕJ3Jü%¨¸5$ãÕJ3JüûÒ£DnYÉ%Í1/9$äZÕJ3FJnY­%×Å$Zâú83FÕJ%A¼U$Õú8Â¾õ.0/#%¶áÃ@$hCUªÕJ3Jü%zåÁ$]3FÕJ%°Ì[x$~Ú3FÕJ%LáÙ$vãÕJqñ$î3JnY­%½ê0<$ZâÕJ3Jü%°nì$¨áÕJ3Jü%åÄÙ$äZÕJ3Jü%ØÌ6ô$ý43FÕJ%ÛÓ$*M%1ü

ké9&+*+

6ç$b¥ÕJ3Jü%ß$ý43FÕJ%$)M%?Ó

&+**

ÝÑ

ÛÓ

$(M%Aü

&+*)Ä÷$8-rBõ7j<õ.0/#%Êçø?$gÕJ3Jü%¿¹$ÕÕJòÅþõnY­%©$xÎÕJ3Jü%
lô$b¥ÕJÅÔ's3JnY­%
ß$82';ÅnY­%ù9l$äZâ8dõ7%ï·Ä$ö²3FÕJ%ÿ1

1Ï

D?$äZÕJ3Jü%ÇÌ

A$e*ÕJ3Jü%{$)3FÕJ%P9

$Õú8Â¾õ.0/#%$+M%4

Äó$åáJ>"l;ÅÕJ3Jü%&*)*§Ñ *#1Çj+,-/."i\$#*N$?Ñ

&**%vt#1èÃI3Ið$¸

Ø$#ÃÃI3Ið$«#ýl@'ÃI3Iðó3Ii\$K¸ 4ë#Z(õÃI3Ið$

BÖ

a

µÖ

þã#'+,-/."é6$

Çz#1Çj+,-/."$
ã#_3CÃI¼~3,-/."$

6! Ü#>ê'ÃI3Ið$|§%5#ÙÔÃI3Ið$

É¾

Öü

W#|Ç3CÃI$ÊÑQZ$#_3CÃI¼~3,-/."$¤"²T#ÕúÃI3Ið$y4[ü

tÆ#eâÃI3Ið$<Öoë#Õ]3CCÃI3Iðî½é6$®

ÏØ#]ÒÃI3Iðî½é6$¡w#Ð×ÃI3Ið$#Õ]Ò'cé6$öþ#1Çj+,-/."$#&%N$Þ" ¢#{¸3CÃI$
»

&**&

¿Ñ

}#ÙÔÃI3Ið$!Å¥ë#ÃÃIæ³òéi\$ÈÑÔÍZþ#ÔÃI3Ið$ÑÉ )5#©LÃIái\$Ó^

5f#Î]ÃI3Ið$ÉÔ¹#ýl@ÃI3Ið$©Í%0#û3CÃI$´¾

Â#bÃI³Àùn3Ii\$

H³;#ÕEÃI3Ið$k¨ß#'é6b+,-/."$

ÖüÿÆ#1Ç3CÃI$ºk

Qç#bÃI3Ið$

­Å

T#'

2Ö

ë#1Çj+,-/."i\$

Y

#&&N$

3,i\-/."$

S#bÃI³Àùn3Ii\$¸1#¨ÃI3Ið$d:¦ô#|Ç3CÃI$BÖ!¾t0#Õ]3CÃI$D"ø#RíÃI3Ið$/!

3#qÃI3Ið$ÑÉ-þ#Õ]Ò'cé6$

ô4

ZO#Õ]ÃI3Ið$ª

Ux#Ãì'°¬é-/."$

Ö9"#û3CÃIî½+,i\$¨ë#uÔÃIkä÷à3Ii\$%#Pi!Pi\$p#Ãó3CÃI$åÔ$#ÝüÃI3Ið$Û£#ýl@ÃI3Ið$q±#]Òì'3CÃI$#-Ü0#ýl@'ÃI3Ið$¶Äm#_j'+,-/."$

vß#'+,-/."É=é6$#&'N$Gk¨þ#ÌÃI3Ið$h¤)ß#ËÃI3Ið$

D¾

8Ü#ú&i\é6$XÈ

g#!f2+,-/."$!ü

2ç#ÃÃIæ³òéi\î½é6$

MN

5#úEØÃI3Iðî½Pi\·$&**'`7 -ç#]ÒÃI3Ið$

&**(

Ö

V³#Ãó3CÃI$6ï T$#aÄÃI+,i\$·JÑ¢#©LÃI3Ið$Ó4

Ú- ¨$#Õ]3CCÃI3Ið$´¾

r#ÕEÃI3Ið$A

YFÂ¨#ýl@ÃI3IðéÁ¯ni\·$Ã7

Â+#?ÃI3Ið$s#aÄÃI3Ið$0ð .#ñÔj'3CÃI$¨z#Õ]Ò'cé6$
#Ãì'°¬é-/."$

%++&

&

nL#Á23.417FÓO$-ç¼#jM[¥ÓO7Oÿ$#%&R$gs2#¯JÓOýÌ+£ø;$¬Ù

I#Wo!Wo`ª$q

ó#ßaÓO7Oÿ$>ãÀ¯#aåüB7FÓO$þ

Yï#-MìÓO7OÿýÌWo`Å$ÕÍæãE¯#éaÓO7Oÿ$

u8

JJ#éaåBfø;$ûã

Tú#cpB,-/40"o`ª$ÛÍb9#éa7FFÓO7Oÿ$Qã>##Wo!WCOD)/40"$$Aà#ÓüB»µø/40"$$A³S#aåÓO7Oÿ$.

«[#é-ÓODG7Oo`ª$]ã°ï#3tBÓO7OÿøÑºwo`Å$Ê<

iK#Wo!WCOD)/40"$

ÙãL#B,-/40"Û?ø;$#%'R$Í½ð#aåÓO7Oÿ$AãÈ#e¡ÓO¿Ð,w7Oo`ª$ÄPÀ9#é-ÓO7Oÿ$\Ø]#/7FÓO7Oÿ$

%++'

%++(

#JGpB7FÓO$¬; ×÷#-MìÓO7Oÿ$·0

á#_7FÓO$¾6 r#dÔÓO,-o`ª$ãÛn9#±QÓO7Oÿ$

Þ

×

±ã

Ò#©âëÓO7Oÿ$ùzì»#3tBÓO7Oÿ$°:#ÚòÓOF®7Ol$

ê0 ¢9#Æ?p,-/40"$;P¯ú#Wo!Wo`ª$



]ã

A0

§

#3tBÓO7OÿýÌø;$#ç7FÓO$­#3tBBÓO7Oÿ"7Oo`ª$#%(R$êÜõt#Bhø;$èããÛ

#@ùBÓO7Oÿ$yú#~çÓOsô(ñ7Oo`ª$

H8

#ÓüB»µø/40"$

É#éaåBfø;$vê¤Ë#ßaÓO¿!}Oo`/40"$ê|#ßaÓO7Oÿ$ã

S#jM[¥ÓO7Oÿ$ÛÍ

#ÝÓO7DZ¦ÖXÓOÿ$êã¨#aåÓOÓO;7Oo`F$

16½[#dÔÓO,-o`ª$

U9ó#7FÓO7Oÿ$²

5I#éaÓO7FOo`ª$;Ç

R#e¡ÓOÓO;¶AOo`F$ÃÇ

#ÓüB»µø/40"$

JO íú#e¡ÓO¿Ð,w7Oo`ª$
%++)

<8

#%)R$6é%++*#aåÓO7Oo`F$

bx#^C%ÓO7Oÿ$ÓÇú#ÚòÓOF®7Ol$¬P k8#7FÓOm=7Oo`ÿ7$8½÷#VÂäEø;$ê :#é-ÓODG7Oo`ª$

:

ÏI#

·0

Õ

*9#Wo!WCOD)/40"$

×7FÓO$

nH#éaÓO7FOo`ª$Î@öJI#´îÇpB,-/40"$°Í'~#B,-/40"Û?ø;$N_¸=#I7FÓO7Oÿ$K »µ#~çÓO7Oÿ$]Í¯÷#^C%ÓO¿4FOo`ª$ÂN Ý|#B,-/40"o`ª$´'{9#/7FÓO$ãÛJú#e¡ÓO7Oÿ$#%*R$¹u©9#Ó"7FÓO7Oÿ$DÓ#5×p,-/40"o`ª$

&**(

Óp

¢G#?s?¾=@N$$#&(P$ÚÂo
0;
&**)

¨

#&)P$}pç

­#ÍÍN:N$$¯#Á=m+/364"$

7â

ß¾#Sl!Sl_¥$

5#è/ÍNÍN=:Njl_G$®õ#?+/364"ÚBû=$:#8Â:GÍN$:#è`ÍNÍN=:Njl_G$>7

Aõ#Íÿ?º¶û364"$

é

«#

ª#?û=g+/364"$

1:GÍN:N$$Ñ

àï#Í?ÍN:N$$Úç4Â

x<#è`ÍN:N$$äôo¼ü#è`:GGÍNíRl_¥$÷½ú#:GÍN$ýó

±H#7Øm+/364"$

ÃÒ¢#á>-.,Å×¥:Nl_¥$9ns¼#c:GÍN:N$$Í°

lî#èJÍN:N$$

É;

§#iJ[

ÍN:N$$*#ÍN:N$$8 Aþ#Sl!SDNB-364"$
&***

;°

¢ú#ÍÍNÍN=$#&*P$ÍÎ

#wçÍNoö,ð:Nl_¥$FIÒ9|#wçÍN:N$$

H°:#iJ[ ÍN:N$ÀÕ:GNl_¥$´K<<#`åÍN1052l_¥$âÚ¤#/JêÍN:N$$

}

ß#

æâ

¼Ç#²OÍN:N$$7â

»#è`:GGÍNíRl_¥$

3Ì

¬X#`åÍN:N$$uâÜ#fÏÍN+/l_¥$³I ]A#U!ÍN:N$$\Y

ÐQ#I:GÍN$C7½A#eWÍN:N$$

ãL
'%%%

;°

1:GÍN$##gÍN¾Ë.q:Nl_¥$¼#fÏÍN:N$$#'%P$H7 'þ#?h2û=$]+ ë#iJ[

ÍN:N$$¨¿';#:GÍNÍ^:B364"$

õ#fÏÍN+/l_¥$âÚ{<#`åÍNÍN=$Ú7 #gÍNÍN=$ø7

bþ#Sl!Sl_¥$

%2

®É

é

'%%&

N#è/ÍNFF:Nl_¥$tEï#wçÍNoö,ð:Nl_¥$\âØï#è`:GÍN$

Ê#Sl!Sl_¥$#'&P$)7 rÖ#gÍNÍN=$5#ÙòÍNE©:Nj$\Â#ÍÍNÍN=$è

¢'#iJ[

ÍN:N$$¨D ú#dm?+/364"$KÝaTw#I:GÍN$}a£#è`ÍN:N$"Èû=$âo

y#è`ÍN:GNl_¥$d6

ÛC#/JêÍNÍN=$Þy·#}Øm?ÚBû=$ÚçM#]@(ÍN:N$$

7ç
ÉL
¹
'%%'

µì6´>#è`:GGÍN:NÆ~l_G$â

õ#ÍÍNù¾&ûl_¥$Äz#è`¦:GÍNñµk364"$®ª±#gÍN:BZ¡ÔVÍN$$

2

õv#

Aé

Ä:#I:GÍN$

1:GÍN$¸#?+/364"l_¥$x¢#/JêÍNÍN=$&%%&

M/ ªV#¬ßçÏK9Kû$#&&N$C&%%'À8#Æ9HÏK$`&#dÐÏK/2o]­$!ÛÂ#Ïø7¿¼ö354"$´* µì#§ÏK9Kû$#&'N$»à&%%(®/J#ÖðÏK<¯9Kl$ëshî#Ïø7¿¼ö354"$!:

÷#Ro!Ro]­$)|

2#jAY¨ÏK9Kû${#äÏKö>$I/

Gþ#äÏKÏK>9KÉo]H$

hî#Ro!RFK9%354"$=#e£ÏKö>$þh#_âÏK9Kû$×ä

uÑ ?[#7Òp/2354"$ÁºÂ¢#e£ÏKÄÎ'z9Ko]­$*gÑ±,#7¿;99354"$ïÙ#8;ÏK9Kû$

Þ~#å_ÏK9KûúËö>$ãE

#dÐÏKÏK>$"- O÷#dÐÏK9KûúËö>$òs

=#b9HÏK$ØÑÆ}W#+uEÏK9KûúËö>$?Ä

ÏX#Ï7ÏKÏK>$;·=#å(ÏK9Kû$í/Jî#Ï7ÏKÏK>$Ç* ¤=#ÏÏKÏK>$:´

h#ÒÏK9Kû$Ïå,#Ïø7¿¼ö354"$

§#å_â7fö>$

Bà ,[#Ïø7$#nÉ99354"$

ÕêÊ#»w99354"$

ýD ?.#ÿv9HÏK$æ:Â¼#å_99354"$<*´/

Ãµ#Ïø7¿¼ö354"$^¦

è#cU×BaûP354"$®;

#é:p79HÏK$=#ØÏK9Kû!KûúËö>$#&+N$ñEsn#Ro!1,ö>$@²õ#í*9HÏK$Ý#S¡9HÏK9Kû$«#jAY¨ÏK9Kû$Å#ip7×Bö>$°#7/2354"×Bö>$Ú+¥==#å_ÏK9KûúËö>$µÜ#å_â7fö>$¸Ó

4î#äÏK9Kû!KûúËö>$q²:#dÐÏK9KûúËö>$/

6u#7/2354"×Bö>$LÓ

Z#e£ÏKÏK>$ôÑA¢#+uEÏK9Kû$Õä¶~#Ro!1,ö>$³Ì ##7/2354"åö>$r3:#dÐ9HÏK$Z

áC ±õ#(6ÏK9Kû$#&,N$¸Ó 4î#äÏKÏK>$&%%-Âó#jAY¨ÏK9Kû$¾

#&*N$Íà

&%%,wà

I/ ì#5ÏK9Kû$#&)N$@ã&%%+

j=#å_â7fö>$

tQ

à×

&%%*

`

Èµ#å_ÏK9Kû$#&(N$Ã\&%%)®Ç?>#(6ÏKåö>$Ô=#dÐÏKÏK>$©½0.1#e£ÏKö>$#&-N$!à
ØÑÆ

kY#TùÏKÏK>$*à/¹y#ÖðÏKÏK>$×º

Âì#Ï99354"$

m#å_ÏKÏK>$üûx>#å_â7fö>$\à&#jAY¨ÏK0Kû$
ó#ÏÏKÏK>$

'%&%

á

·#Ì7GÌO$ÁÃJè#ä7u27GÌO$©

¶:#Â.ÌOÌO;$Ï

A#<Hu27GÌO$ÖÝ#o>[§ÌO7Oø$âw[è#ÌÌOÌO;$| <)#VöÌO7Oø$|>/#ÌÌOÌO;7Opt_G$\Ñ=#o>[§ÌO7Oø$Ç:#kéÌOÌO;7Opt_G$âÏ<½#2ñ;W" ½&#Ìõ2»·ñ132"$^Ý}#ÔÌOñ;$^Ý[#àÌOwíþÄ7GOt_¬$

v8

ßð#áÿÌOñ;$Eq#ÿ1ÌO7Oø$
P¿

<ë#U

X#,0t_L+&ñ;$â#!7GÌO$@( ½~#4Ðu,0132"Ò@ñ;$c¦Û#Ìõ2»·ñ132"$ÏB

"R®#á`ÞrÔ¢76132"t_¬$±( M1#o>[§ÌOñ;$Ê³>£#hÎÌO¼mNG$

8³l#ÐÌOb9t_ø$C>#i¤ÌOñ;$#((Q$Is#$xD2ÌOÌO;7Ot_G$ÿdÃÛ#ÌÌOÌO;7Opt_G$

ÝÚ:#]3ûÌO7Oø$à'ó#hÎ7GÌOÆ7Ot_¬$¡Êa#z76132"!Ò,0132"$*´¨ý#$xD2ÌOñ;$Tc#(%Q$¯'%&&#(&Q$Ù

'%&'<" ¦4#f7GÌO$#('Q$­¿

'%&(

'%&)

(E

#()Q$­¿
c'%&*¶£#ùyu2,0132"$Ì76132"$

7GÌO7Oø$#o>[§ÌO7Oø$ï#Ìõ2»·ñ132"$

O#Ìõ2»·ñ132"$­

6,#o>[§ÌO7Oø$X#,0t_L+&ñ;$#w[è#«ÜãÌO7Oø$µ#áÿÌOF97Ot_¬$ÏånK#ÐÌO7Oø÷Èñ;$ë]#Ì2ÌOÌO;7Ot_G$ôÝÕ·#Aò2ÌOÌO;7Ot_G$ÒÅæÏ

Ë¸#á`ÌO7Oø÷Èñ;$ÔÏÃÌ:;#ùyu2-./ñ;$Áë?#ÿ1ÌO7Oø$î*

0#o>[§ÌO7Oø$ìÁ#gYÌO7Oø$#(*Q$18 =ú#S¿7GÌO$'%&+#`Þõ27GÌO$ÓÌ5#,0t_L+&ñ;$åâ

2e#ÀBu2ÀB,0132"$¿Ýª#ÌÌO7Oø÷Èñ;$8-{#j"ÌOÌO;¾%GOt_ø$¹à

<#ÌÌOÌO;7Opt_G$­²

Z°#á`ÌO7GOt_¬÷Èñ;$5×#á`ÌOÌO;7Opt_G$#(+Q$ê

#i¤ÌOÌO;$ºÊlç;#Ìõ2»·ñ132"$Í|¥#ÌÌO7Opt_G$âü¸#Ì7GÌO÷Èñ;$ÅÝ

5#âÝür?¾ÌO$Ø

É#,0t_L+&ñ;$6Sx¨D2KH

+._

+(+l*, Zw
+(+l+) s

"

s

!

#

q[u

6S|^x¨ngu o a 4£3tQ<E\dC4`33=:G;!
')+-&((.) irjep)&*/&TUVW+1,-*.&.,0+©$(+%

Zw~ XkZw¡D¥DY2O3ER¢@"ycb35BO
 CL>?Jy#;O8AE" §@IMP=tR
7"v{4LF}{Dm¦D]CBNG;D@"¤I
zDhRfI?\93!