Dottessa Iris Parrini

Z/dD/͗

hEEhKsKW/dK>K

E>>Z/KdK^^//d͛

Dottessa Iris Parrini

Ospedale Mauriziano Torino

ŽŵĂŶĚĞ͗

`ŽŵĞƐŝĚĞĨŝŶŝƐĐĞŝůYd

`WĞƌĐŚĠŝůYdůƵŶŐŽĐŝĨĂƉĂƵƌĂ

`YƵĂůŝƐŽŶŽůĞĐĂƵƐĞĚŝYdůƵŶŐŽ

`ŚĞĐŽƐĂĨĂƉƌĞĐŝƉŝƚĂƌĞƵŶƋƵĂĚƌŽĚŝYdůƵŶŐŽ

͛ů͛ĞƐƉƌĞƐƐŝŽŶĞĚĞůůĂƌŝƉŽůĂƌŝnjnjĂnjŝŽŶĞ

ŵŝŽĐĂƌĚŝĐĂǀĞŶƚƌŝĐŽůĂƌĞ

ŽŵĞƐŝĚĞĨŝŶŝƐĐĞŝůYd͍

ŝĐŽƐĂŚŽďŝƐŽŐŶŽ͗

` 'ŝŶϭϮĐŽŶŝůĐĂůĐŽůŽĚĞůYdĐŽƌƌĞƚƚŽ

sĂůŽƌŝ ŶŽƌŵĂůŝƉĞƌůĂĚŝĂŐŶŽƐŝĚŝYdůƵŶŐŽ

ƵƚŝůŝnjnjĂŶĚŽůĂĨŽƌŵƵůĂĚŝ ĂnjĞƚƚ͛Ɛ

^ĞƐƐŽ ŵĂƐĐŚŝůĞ ^ĞƐƐŽ ĨĞŵŵŝůĞ

EŽƌŵĂůĞ фϰϯϬ ŵƐĞĐ фϰϱϬ ŵƐĞĐ

ŽƌĚĞƌůŝŶĞ ϰϯϬʹϰϱϬ ŵƐĞĐ ϰϱϬʹϰϳϬ ŵƐĞĐ

WƌŽůƵŶŐĂƚŽ хϰϱϬ ŵƐĞĐ хϰϳϬ ŵƐĞĐ

WĞƌĐŚĠŝůYdůƵŶŐŽĐŝĨĂƉĂƵƌĂ

/E

OUT K Ca

Na Accumulo di calcio

(esacerbato da

catecolamine)

^/EKW

DKZd/DWZKss/^

ŚŝğĂƌŝƐĐŚŝŽ

Z/KWd/͗

/^,D/

/>dd/s

/WZdZK&/

'Ed/

hKZ^EK

Yh>/^KEK>h^͗EhDZK^/&ddKZ/WK^^KEK

/EdZ&Z/ZdZD/EEKhE>>h'DEdK>Yd

KE//KE/KͲ^/^dEd/

KDW>/E

KZZ>d

>>dZW/

KEK>K'/

dZW/KEKD/dEd/

dZW/

Ed/EZK

QT

prolungato

EhDZK^/&ddKZ/WK^^KEK/EdZ&Z/ZdZD/EEK

hE>>h'DEdK>Yd

KE//KE/KͲ^/^dEd/

KDW>/E

KZZ>d

>>dZW/

KEK>K'/

dZW/

KEKD/dEd/

dZW/

Ed/EZK

QT prolungato

ƒ ĞƚăĂǀĂŶnjĂƚĂ

ƒ ƐĞƐƐŽĨĞŵŵŝŶŝůĞ

ƒ ŝƉŽƚŝƌŽŝĚŝƐŵŽ

ƒ ^ŝŶĚƌŽŵĞĚĞůYdůƵŶŐŽĐŽŶŐĞŶŝƚĂ ŵĂůĂƚƚŝĂĐĂƌĚŝĂĐĂ

ƒ ĚŝƐĨƵŶnjŝŽŶĞǀĞŶƚƌŝĐŽůĂƌĞƐŝŶŝƐƚƌĂ

ƒ ŝƐĐŚĞŵŝĂĐĂƌĚŝĂĐĂ

ƒ ďƌĂĚŝĐĂƌĚŝĂ

EhDZK^/&ddKZ/WK^^KEK/EdZ&Z/ZdZD/EEK

hE>>h'DEdK>Yd

KE//KE/KͲ^/^dEd/

,D/KdZW// ,WK^^KEK

dZD/EZhEYd>hE'K

,ŝƐƚŽŶĞ ĚĞĂĐĞƚLJůĂƐĞ ŝŶŚŝďŝƚŽƌƐ sŽƌŝŶŽƐƚĂƚ

DƵůƚŝƚĂƌŐĞƚĞĚ ƚLJƌŽƐŝŶĞŬŝŶĂƐĞ ŝŶŚŝďŝƚŽƌƐ

^ƵŶŝƚŝŶŝď ƐŽƌĂŶĞĨŝď

KDW>/E

KZZ>d

>>dZW/

KEK>K'/

dZW/

KEKD/dEd/

dZW/

Ed/EZK

QT prolungato

ƐŽƌĂŶĞĨŝď

ZͲ>ŝŶŚŝďŝƚŽƌƐ

ĂƐĂƚŝŶŝď EŝůŽƚŝŶŝď sĂŶƚĞŶĂŶŝď

ƌďͲϭͬͲϮƌĞĐĞƉƚŽƌƐŝŶŚŝďŝƚŽƌƐ

>ĂƉĂƚŝŶŝď

WƌŽƚĞĂƐŽŵĞ ŝŶŚŝďŝƚŽƌƐ

ŽƌƚĞnjŽŵŝď DŝƐĐĞůůĂŶĞŽƵƐ

ƌƐĞŶŝĐ ƚƌŝŽdžŝĚĞ

EhDZK^/&ddKZ/WK^^KEK/EdZ&Z/ZdZD/EEK

hE>>h'DEdK>Yd

KE//KE/KͲ

^/^dEd/

ŽŵƉůŝĐĂŶnjĞĐŽƌƌĞůĂƚĞĂůůĂƚĞƌĂƉŝĂ

ŽŶĐŽůŽŐŝĐĂ

ƒ /ƉŽŬĂůĞŵŝĂ͕/ƉŽŵĂŐŶĞƐĞŵŝĂ͕/ƉŽĐĂůĐĞŵŝĂ

ƒ ŝƐĨƵŶnjŝŽŶĞ ĞƉĂƚŝĐĂ ĞƌĞŶĂůĞ

ƒ EĂƵƐĞĂ͕ǀŽŵŝƚŽ͕ĚŝĂƌƌĞĂ

KDW>/E

KZZ>d

>>dZW/

KEK>K'/

dZW/

KEKD/dEd/

dZW/

Ed/EZK

QT prolungato

ƒ EĂƵƐĞĂ͕ǀŽŵŝƚŽ͕ĚŝĂƌƌĞĂ

ƒ ^ĐĂƌƐŽ ĐŽŶƚƌŽůůŽ ŐůŝĐĞŵŝĐŽ

ƒ ĚĞŝĚƌĂƚĂnjŝŽŶĞ͕ĚĞŶƵƚƌŝnjŝŽŶĞ

EhDZK^/&ddKZ/WK^^KEK/EdZ&Z/ZdZD/EEK

hE>>h'DEdK>Yd

KE//KE/KͲ^/^dEd/

&ĂƌŵĂĐŝƉŽƚĞŶnjŝĂůŵĞŶƚĞĂƌŝƐĐŚŝŽĚŝƉƌŽůƵŶŐĂƌĞů͛ŝŶƚĞƌǀĂůůŽYd͘

&ĂƌŵĂĐŝ

ĐĂƌĚŝŽǀĂƐĐŽůĂƌŝ

ŵŝŽĚĂƌŽŶĞ

ŚŝŶŝĚŝŶĂ

ŝƐŽƉŝƌĂŵŝĚĞ

ŽďƵƚĂŵŝŶĂ

ŽƉĂŵŝŶĂ

ĨĞĚƌŝŶĂ

ƉŝŶĞĨƌŝŶĂ

&ůĞĐĂŝŶŝĚĞ /ďƵƚŝůŝĚĞ

&ĂƌŵĂĐŝ^E

ůŽƉĞƌŝĚŽůŽ

ŵŝƚƌŝƉƚŝůŝŶĂ

ŝƚĂůŽƉƌĂŵ

ůŽƌĂůŝŽŝĚƌĂƚŽ

ůŽƌƉƌŽŵĂnjŝŶĂ

ůŽŵŝƉƌĂŵŝŶĂ

ƌŽƉĞƌŝĚŽůŽ

&ĞůďĂŵĂƚŽ

&ůƵŽdžĞƚŝŶĂ 'ĂůĂŶƚĂŵŝŶĂ

KůĂŶnjĂƉŝŶĂ WĂƌŽdžĞƚŝŶĂ YƵĞƚŝĂƉŝŶĂ ZŝƐƉĞƌŝĚŽŶĞ

^ĞƌƚŝŶĚŽůŽ

^ĞƌƚƌĂůŝŶĂ dŝŽƌŝĚĂnjŝŶĂ dŝnjĂŶŝĚŝŶĂ dƌŝŵŝƉƌĂŵŝŶĂ sĞŶůĂĨĂdžŝŶĂ

&ĂƌŵĂĐŝ'/

&ĂƌŵĂĐŝ

ƌĞƐƉŝƌĂƚŽƌŝŽ

^ĂůďƵƚĂŵŽůŽ

^ĂůŵĞƚĞƌŽůŽ dĞƌďƵƚĂůŝŶĂ

&ĂƌŵĂĐŝ

ĂŶƚŝďĂƚƚĞƌŝĐŝ

njŝƚƌŽŵŝĐŝŶĂ

ŝƉƌŽĨůŽdžĂĐŝŶĂ

ůĂƌŝƚƌŽŵŝĐŝŶĂ

ƌŝƚƌŽŵŝĐŝŶĂ

&ĂƌŵĂĐŝ

ĂŶƚŝǀŝƌĂůŝ

ŵĂŶƚŝĚŝŶĂ

&ŽƐĐĂƌŶĞƚ

&ĂƌŵĂĐŝ

ĂŶƚŝƉĂƌĂƐƐŝƚĂƌŝ

ůŽƌŽĐŚŝŶĂ DĞĨůŽĐŚŝŶĂ WĞŶƚĂŵŝĚŝŶĂ

&ĂƌŵĂĐŝ

&ĂƌŵĂĐŝ

ĚĞĐŽŶŐĞƐƚŝŽŶĂŶƚŝ

ŶĂƐĂůŝĞ

ĂŶƚŝƐƚĂŵŝŶŝĐŝ

&ĞŶŝůĞĨƌŝŶĂ

&ĞŶŝůƉƌŽƉĂŶŽůĂŵŝŶĂ WƐĞƵĚŽĞĨĞĚƌŝŶĂ dĞƌĨĞŶĂĚŝŶĂ

ůƚƌŝĨĂƌŵĂĐŝ

ůĨƵnjŽƐŝŶĂ KĐƚƌĞŽƚŝĚĞ

KDW>/E

KZZ>d

>>dZW/

KEK>K'/

dZW/KEKD/dEd/

dZW/

Ed/EZK

QT prolungato /ďƵƚŝůŝĚĞ

/ŶĚĂƉĂŵŝĚĞ /ƐƌĂĚŝƉŝŶĂ DŝĚŽĚƌŝŶĂ EŽƌĞƉŝŶĞĨƌŝŶĂ

^ŽƚĂůŽůŽ

'ĂůĂŶƚĂŵŝŶĂ /ŵŝƉƌĂŵŝŶĂ

>ĞǀŽŵĞƉƌŽŵĂnjŝŶĂ

>ŝƚŝŽ

DĞƚĂĚŽŶĞ DĞƚŝůĨĞŶŝĚĂƚŽ EŽƌƚƌŝƉƚŝůŝŶĂ

&ĂƌŵĂĐŝ'/

ŽůĂƐĞƚƌŽŶ

ŽŵƉĞƌŝĚŽŶĞ 'ƌĂŶŝƐĞƚƌŽŶ KŶĚĂŶƐĞƚƌŽŶ

ƌŝƚƌŽŵŝĐŝŶĂ

>ĞǀŽĨůŽdžĂĐŝŶĂ DŽdžŝĨůŽdžĂĐŝŶĂ KĨůŽdžĂĐŝŶĂ

ŽƚƌŝŵŽƐƐĂnjŽůŽ

&ĂƌŵĂĐŝ

ĂŶƚŝŵŝĐŽƚŝĐŝ

&ůƵĐŽŶĂnjŽůŽ /ƚƌĂĐŽŶĂnjŽůŽ

<ĞƚŽĐŽŶĂnjŽůŽ sŽƌŝĐŽŶĂnjŽůŽ

KĐƚƌĞŽƚŝĚĞ

^ŝďƵƚƌĂŵŝŶĂ dĂĐƌŽůŝŵƵƐ dĂŵŽdžŝĨĞŶĞ sĂƌĚĞŶĂĨŝů

YdĐ ŝŶƚĞƌǀĂůůŽ ĐŽƌƌĞůĂƚŽ ĂůŐƌĂĚŽ Ěŝ ƚŽƐƐŝĐŝƚă

YdĐ ƉƌŽůŽŶŐĂƚŝŽŶ 'ƌĂĚĞ ĞĨŝŶŝƚŝŽŶ

'ƌĂĚĞ / YdĐ хϰϱϬʹ ϰϳϬ ŵƐ

'ƌĂĚĞ // YdĐ хϰϱϬʹϱϬϬ ŵƐŽƌԜхԜϲϬ ŵƐĂďŽǀĞ

ďĂƐĞůŝŶĞ

'ƌĂĚĞ /// YdĐхϱϬϬ ŵƐ

'ƌĂĚĞ/s

YdĐхϱϬϬ ŵƐ͖ůŝĨĞͲƚŚƌĞĂƚĞŶŝŶŐƐŝŐŶƐŽƌ

ƐLJŵƉƚŽŵƐ;ƐLJŶĐŽƉĞ͕ƐŚŽĐŬ͕

ŚLJƉŽƚĞŶƐŝŽŶ͕ĂƌƌŚLJƚŚŵŝĂ͕ŚĞĂƌƚĨĂŝůƵƌĞͿ ŚLJƉŽƚĞŶƐŝŽŶ͕ĂƌƌŚLJƚŚŵŝĂ͕ŚĞĂƌƚĨĂŝůƵƌĞͿ

'ƌĂĚĞ s ĞĂƚŚ

ŽŵŵŽŶƚĞƌŵŝŶŽůŽŐLJ ĐƌŝƚĞƌŝĂ ĨŽƌ ĂĚǀĞƌƐĞ ĞǀĞŶƚƐ ǀϯ͘Ϭ;dͿ͕YdƉƌŽůŽŶŐĂƚŝŽŶ

QTc >500 milliseconds o variazione >60 milliseconds rispetto al basale:

sono i comuni criteri utilizzati quale indice di cardiotossicità

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: The clinical evaluation of QT/QTc prolongation and pro-arrhythmic potential for non-antiarrhythmic drugs: E14. Geneva, Switzerland:

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2005.

Available at: http://www.ich.org/LOB/media/MEDIA1476.pdf. Last accessed July 22, 2010.

WZ/D/K'E/dZddDEdK,D/KdZW/K

'ϭϮZ/s/KE/

ŽŶƐŝŐůŝĂƚŝϯ'ĂĚŝƐƚĂŶnjĂĚŝϭϬŵŝŶƵƚŝ YdĐхϰϳϬŵƐĞĐ /^d/dh/ZD/^hZKZZdd/s

ƒ KEdZK>>KZd/E/E͕D'E^/K͕>/K͕^K/KWKd^^/K

ƒ KZZ''Z>ddZK>/d/;<н хϰDYͬ>͕DŐн хϭ͕ϴŵŐͬĚ>Ϳ

ƒ ^K^WEZ&ZD/KEKD/dEd/,WK^^KEKdZD/EZhE

>>hE'DEdK>Yd

• Z/s>hdZYdĐ WZ/D/ /E//ZdZddDEdK

• s>hdZZ/^,/KͬE&//K

WƌŽůŽŶŐĞĚYdĐ /ŶƚĞƌǀĂůŝŶĂŶĐĞƌdŚĞƌĂƉĞƵƚŝĐƌƵŐĞǀĞůŽƉŵĞŶƚ͗

ĞĨŝŶŝŶŐƌƌŚLJƚŚŵŝĐZŝƐŬŝŶDĂůŝŐŶĂŶĐLJ͕:ŽĂŶŶĂ D͘ƌĞůů WƌŽŐƌĞƐƐŝŶĂƌĚŝŽǀĂƐĐƵůĂƌŝƐĞĂƐĞƐϱϯ;ϮϬϭϬͿϭϲϰʹϭϳϮ

hZEd/>dZddDEdK

'ϭϮZ/s/KE/

ƒ ^dZddKDKE/dKZ''/K'>/>ddZK>/d/

ƒ KZZ''Z/^KE/;<н хϰDYͬ>͕DŐн хϭ͕ϴŵŐͬĚ>Ϳ

ƒ ddE/KE>>dZW/KEKD/dEd/,WK^^KEK

>>hE'ZYd

ŽƉŽƚƌĂƚƚĂŵĞŶƚŽ͗

KŐŶŝϭϬŵƐ ĂƵŵĞŶƚĂŶŽŝůƌŝƐĐŚŝŽĚŝdĚW ĚĞůϱͲϳй͗

YdĐ ϱϰϬŚĂхƌŝƐĐŚŝŽĚŝϲϯͲϵϳйƌŝƐƉĞƚƚŽĂϰϰϬ

YdĐ хϱϬϬŵƐ

YdĐ нϲϬŵƐ ƌŝƐƉĞƚƚŽĂůďĂƐĂůĞ

ƒ KE^/ZZK^W>//KE

ƒ KZZ''Zdhdd//WK^^//>/&ddKZ// Z/^,/K

Z/^,/K>sdK

'ϭϮZ/s/KE/

YdĐ хϱϬϬŵƐĞĐ ŽхϲϬŵƐĞĐ ƌŝƐƉĞƚƚŽĂůďĂƐĂůĞ

ƒ KZZ''Zdhdd//WK^^//>/&ddKZ// Z/^,/K

ƒ DĂŶƚĞŶĞƌĞ<н хϰDYͬ>͕DŐн хϭ͕ϴŵŐͬĚ>

ƒ ƐŽƐƉĞŶĚĞƌĞĨĂƌŵĂĐŝĐŽŶĐŽŵŝƚĂŶƚŝĐŚĞƉŽƐƐŽŶŽĂůůƵŶŐĂƌĞŝůYd

ƒ ^KDW/KEK^/EdKD/^K^WEZ>dZW/KEK>K'/

ƒ KWKKZZ/KE/&ddKZ/WZ/^WKEEd/͛WK^^//>

Z/WZEZ>dZW/ĐŽŶĚŽƐĂŐŐŝŽƌŝĚŽƚƚŽ^YdĐ фϰϳϬŵƐĞĐ ƉƌŽƐĞŐƵĞŶĚŽŵŽŶŝƚŽƌĂŐŐŝŽ

ƒs>hdZZ/^,/KͬE&//K

ůŝŶ WŚĂƌŵĂĐŽů dŚĞƌ͗ϮϬϭϬ&Ğď͖ϴϳ;ϮͿ͗ϭϲϲͲϳϰ͘ĚŽŝ͗ϭϬ͘ϭϬϯϴͬĐůƉƚ͘ϮϬϬϵ͘Ϯϭϰ͘ƉƵď ϮϬϬϵĞĐϵ͘ ǀĂůƵĂƚŝŽŶ ĂŶĚ ŵĂŶĂŐĞŵĞŶƚ ŽĨ ĐĂƌĚŝĂĐ ƐĂĨĞƚLJ ƵƐŝŶŐ

ƚŚĞ ĞůĞĐƚƌŽĐĂƌĚŝŽŐƌĂŵ ŝŶ ŽŶĐŽůŽŐLJ ĐůŝŶŝĐĂů ƚƌŝĂůƐ͗ ĨŽĐƵƐ ŽŶĐĂƌĚŝĂĐ ƌĞƉŽůĂƌŝnjĂƚŝŽŶ ;YdĐ ŝŶƚĞƌǀĂůͿ͘ DŽƌŐĂŶƌŽƚŚ :͕ ^ŚĂŚZZ͕ ^ĐŽƚƚ:t

KE>h^/KE/ʹ ϭ

'ĞƐƚŝŽŶĞͲ WƌĞǀĞŶnjŝŽŶĞ

• /ĚĞŶƚŝĨŝĐĂƌĞƉĂnjŝĞŶƚŝĂĚĂůƚŽƌŝƐĐŚŝŽĂƉƌŝŽƌŝ

• ůŝŵŝŶĂƌĞƚƵƚƚĞůĞĐŽŶĚŝnjŝŽŶŝĐŚĞĂŐŝƐĐŽŶŽƐƵů

ƉƌŽůƵŶŐĂŵĞŶƚŽĚĞůůĂƌŝƉŽůĂƌŝnjnjĂnjŝŽŶĞ

• WƌŝŵĂĚŝƐŽƐƉĞŶĚĞƌĞƵŶĂƚĞƌĂƉŝĂƐĂůǀĂǀŝƚĂ͕ĞůŝŵŝŶĂƌĞ

• WƌŝŵĂĚŝƐŽƐƉĞŶĚĞƌĞƵŶĂƚĞƌĂƉŝĂƐĂůǀĂǀŝƚĂ͕ĞůŝŵŝŶĂƌĞ

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ĚŝŝŶƚĞƌĂnjŝŽŶŝƐƵĐŝƚŽĐƌŽŵŝͿ

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WĂnjŝĞŶƚĞŚĂŝůYdůƵŶŐŽ͗

• DŽŶŝƚŽƌŝnjnjĂnjŝŽŶĞ

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dŽƌƐŝŽŶĞĚŝWƵŶƚĂ

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ƒ ĨĂƌŵĂĐŝ

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ĐŽŝŶǀŽůŐŝŵĞŶƚŽĐĂƌĚŝĂĐŽĚĞůƚƵŵŽƌĞ

ƒ 'ĂϭϮĚĞƌŝǀĂnjŝŽŶĞ

ƒ ƐƚŽƌŝĂƉĞƌƐŽŶĂůĞĞĨĂŵŝŐůŝĂƌĞĚŝŵĂůĂƚƚŝĂĐĂƌĚŝĂĐĂ

ƒ ĞǀŝƚĂƌĞĨĂƌŵĂĐŝĐŚĞŝŶĚƵĐŽŶŽďƌĂĚŝĐĂƌĚŝĂ

ƒ ĐŽŶƚƌŽůůŽ ĞůĞƚƚƌŽůŝƚŝ

ŽŵĞƉƌĞǀĞŶŝƌĞ͍

d,>/KD/

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;ĂŶŐŝŽŐĞŶĞƐŝƐ ŝŶŚŝďŝƚŽƌͿ ƒ KƌŵŽŶŝƚŝƌŽŝĚĞŝ

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ĚĞůůĂĐŽŶĚƵnjŝŽŶĞĚŝďĂƐĞ͕ŵŽŶŝƚŽƌĂŐŐŝŽ'Ğ

ƉƌĞƐƐŝŽŶĞĂƌƚĞƌŝŽƐĂĚƵƌĂŶƚĞůĞƉƌŝŵĞŽƌĞĚŝ

ŝŶĨƵƐŝŽŶĞ

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ĐŽŶĐŽƌƚŝĐŽƐƚĞƌŽŝĚŝ

Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy:

diagnosis, pathogenesis, and management. Circulation 2004;109:3122–31

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ƒ ƐĞŝƐŝŶƚŽŵŝƐŽŶŽůĞŐĂƚŝĂůůĂďƌĂĚŝĐĂƌĚŝĂ͕ƉƌĞŶĚĞƌĞ

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ƒ WDƐĞs///

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Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy:

diagnosis, pathogenesis, and management. Circulation 2004;109:3122–31

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