����JFIFXX�����    $.' ",#(7),01444'9=82<.342  2!!22222222222222222222222222222222222222222222222222����"��4�� ���,�PG"Z_�4�˷����kjز�Z�,F+��_z�,�© �����zh6�٨�ic�fu���#ډb���_�N�?��wQ���5-�~�I���8����TK<5o�Iv-�����k�_U_�����~b�M��d����Ӝ�U�Hh��?]��E�w��Q���k�{��_}qFW7HTՑ��Y��F�?_�'ϔ��_�Ջt��=||I ��6�έ"�����D���/[�k�9���Y�8ds|\���Ҿp6�Ҵ���]��.����6�z<�v��@]�i%��$j��~�g��J>��no����pM[me�i$[����s�o�ᘨ�˸ nɜG-�ĨU�ycP�3.DB�li�;��hj���x7Z^�N�h������N3u{�:j�x�힞��#M&��jL P@_���� P��&��o8������9�����@Sz6�t7#O�ߋ �s}Yf�T���lmr����Z)'N��k�۞p����w\�Tȯ?�8`�O��i{wﭹW�[�r�� ��Q4F�׊���3m&L�=��h3����z~��#�\�l :�F,j@�� ʱ�wQT����8�"kJO���6�֚l����}���R�>ډK���]��y����&����p�}b��;N�1�m�r$�|��7�>e�@B�TM*-iH��g�D�)� E�m�|�ؘbҗ�a��Ҿ����t4���o���G��*oCN�rP���Q��@z,|?W[0�����:�n,jWiE��W��$~/�hp\��?��{(�0���+�Y8rΟ�+����>S-S����VN;�}�s?.����� w�9��˟<���Mq4�Wv'��{)0�1mB��V����W[�����8�/<� �%���wT^�5���b��)iM� pg�N�&ݝ��VO~�q���u���9� ����!��J27����$O-���! �:�%H��� ـ����y�ΠM=t{!S�� oK8������t<����è:a������[�����ա�H���~��w��Qz`�po�^ ����Q��n� �,uu�C�$ ^���,������8�#��:�6��e�|~���!�3�3.�\0��q��o�4`.|� ����y�Q�`~;�d�ׯ,��O�Zw�������`73�v�܋�<���Ȏ�� ـ4k��5�K�a�u�=9Yd��$>x�A�&�� j0� ���vF��� Y�|�y��� ~�6�@c��1vOp�Ig����4��l�OD���L����� R���c���j�_�uX6��3?nk��Wy�f;^*B� ��@�~a�`��Eu������+���6�L��.ü>��}y���}_�O�6�͐�:�YrG�X��kG�����l^w���~㒶sy��Iu�!� W ��X��N�7BV��O��!X�2����wvG�R�f�T#�����t�/?���%8�^�W�aT��G�cL�M���I��(J����1~�8�?aT ���]����AS�E��(��*E}� 2��#I/�׍qz��^t�̔���b�Yz4x���t�){ OH��+(E��A&�N�������XT��o��"�XC��'���)}�J�z�p� ��~5�}�^����+�6����w��c��Q�|Lp�d�H��}�(�.|����k��c4^�"�����Z?ȕ ��a<�L�!039C� �Eu�C�F�Ew�ç ;�n?�*o���B�8�bʝ���'#Rqf���M}7����]����s2tcS{�\icTx;�\��7K���P���ʇ Z O-��~��c>"��?�������P��E��O�8��@�8��G��Q�g�a�Վ���󁶠�䧘��_%#r�>�1�z�a��eb��qcPѵ��n���#L��� =��׀t� L�7�`��V���A{�C:�g���e@�w1 Xp3�c3�ġ����p��M"'-�@n4���fG��B3�DJ�8[Jo�ߐ���gK)ƛ��$���� ���8�3�����+���� �����6�ʻ���� ���S�kI�*KZlT _`���?��K����QK�d����B`�s}�>���`��*�>��,*@J�d�oF*����弝��O}�k��s��]��y�ߘ��c1G�V���<=�7��7����6�q�PT��tXԀ�!9*4�4Tހ3XΛex�46���Y��D ����� �BdemDa����\�_l,��G�/���֌7���Y�](�xTt^%�GE�����4�}bT���ڹ�����;Y)���B�Q��u��>J/J �⮶.�XԄ��j�ݳ�+E��d ��r�5�_D�1 ��o�� �B�x�΢�#���<��W�����8���R6�@g�M�.��� dr�D��>(otU��@x=��~v���2� ӣ�d�oBd��3�eO�6�㣷�����ݜ6��6Y��Qz`��S��{���\P�~z m5{J/L��1������<�e�ͅPu�b�]�ϔ���'������f�b� Zpw��c`"��i���BD@:)ִ�:�]��hv�E�w���T�l��P���"Ju�}��وV J��G6��. J/�Qgl߭�e�����@�z�Zev2u�)]կ�����7x���s�M�-<ɯ�c��r�v�����@��$�ޮ}lk���a���'����>x��O\�ZFu>�����ck#��&:��`�$�ai�>2Δ����l���oF[h��lE�ܺ�Πk:)���`�� $[6�����9�����kOw�\|���8}������ބ:��񶐕��I�A1/�=�2[�,�!��.}gN#�u����b��� ~��݊��}34q����d�E��Lc��$��"�[q�U�硬g^��%B �z���r�pJ�ru%v\h1Y�ne`ǥ:g���pQM~�^�Xi� ��`S�:V29.�P���V�?B�k�� AEvw%�_�9C�Q����wKekPؠ�\�;Io d�{ ߞo�c1eP����\� `����E=���@K<�Y���eڼ�J���w����{av�F�'�M�@/J��+9p���|]�����Iw &`��8���&M�hg��[�{��Xj��%��Ӓ�$��(����ʹN���<>�I���RY���K2�NPlL�ɀ)��&e����B+ь����( � �JTx���_?EZ� }@ 6�U���뙢ط�z��dWI�n` D����噥�[��uV��"�G&Ú����2g�}&m��?ċ�"����Om#��������� ��{�ON��"S�X��Ne��ysQ���@Fn��Vg���dX�~nj�]J�<�K]:��FW��b�������62�=��5f����JKw��bf�X�55��~J �%^����:�-�QIE��P��v�nZum� z � ~ə ���� ���ة����;�f��\v���g�8�1��f24;�V���ǔ�)����9���1\��c��v�/'Ƞ�w�������$�4�R-��t���� e�6�/�ġ �̕Ecy�J���u�B���<�W�ַ~�w[B1L۲�-JS΂�{���΃������A��20�c#��@ 0!1@AP"#2Q`$3V�%45a6�FRUq��� ����^7ׅ,$n�������+��F�`��2X'��0vM��p�L=������5��8������u�p~���.�`r�����\���O��,ư�0oS ��_�M�����l���4�kv\JSd���x���SW�<��Ae�IX����������$I���w�:S���y���›R��9�Q[���,�5�;�@]�%���u�@ *ro�lbI �� ��+���%m:�͇ZV�����u�̉����θau<�fc�.����{�4Ա� �Q����*�Sm��8\ujqs]{kN���)qO�y�_*dJ�b�7���yQqI&9�ԌK!�M}�R�;������S�T���1���i[U�ɵz�]��U)V�S6���3$K{�ߊ<�(� E]Զ[ǼENg�����'�\?#)Dkf��J���o��v���'�%ƞ�&K�u�!��b�35LX�Ϸ��63$K�a�;�9>,R��W��3�3� d�JeTYE.Mϧ��-�o�j3+y��y^�c�������VO�9NV\nd�1 ��!͕_)a�v;����թ�M�lWR1��)El��P;��yوÏ�u 3�k�5Pr6<�⒲l�!˞*��u־�n�!�l:����UNW ��%��Chx8vL'��X�@��*��)���̮��ˍ��� ���D-M�+J�U�kvK����+�x8��cY������?�Ԡ��~3mo��|�u@[XeY�C�\Kp�x8�oC�C�&����N�~3-H���� ��MX�s�u<`���~"WL��$8ξ��3���a�)|:@�m�\���^�`�@ҷ)�5p+��6���p�%i)P M���ngc�����#0Aruz���RL+xSS?���ʮ}()#�t��mˇ!��0}}y����<�e� �-ή�Ԩ��X������ MF���ԙ~l L.3���}�V뽺�v�����멬��Nl�)�2����^�Iq��a��M��qG��T�����c3#������3U�Ǎ���}��לS�|qa��ڃ�+���-��2�f����/��bz��ڐ�� �ݼ[2�ç����k�X�2�* �Z�d���J�G����M*9W���s{��w���T��x��y,�in�O�v��]���n����P�$�JB@=4�OTI�n��e�22a\����q�d���%�$��(���:���: /*�K[PR�fr\nڙdN���F�n�$�4�[�� U�zƶ����� �mʋ���,�ao�u 3�z� �x��Kn����\[��VFmbE;�_U��&V�Gg�]L�۪&#n%�$ɯ�dG���D�TI=�%+AB�Ru#��b4�1�»x�cs�YzڙJG��f��Il��d�eF'T� iA��T���uC�$����Y��H?����[!G`}���ͪ� �纤Hv\������j�Ex�K���!���OiƸ�Yj�+u-<���'q����uN�*�r\��+�]���<�wOZ.fp�ێ��,-*)V?j-kÊ#�`�r��dV����(�ݽBk�����G�ƛk�QmUڗe��Z���f}|����8�8��a���i��3'J�����~G_�^���d�8w������ R�`(�~�.��u���l�s+g�bv���W���lGc}��u���afE~1�Ue������Z�0�8�=e�� f@/�jqEKQQ�J��oN��J���W5~M>$6�Lt�;$ʳ{���^��6�{����v6���ķܰg�V�cnn �~z�x�«�,2�u�?cE+Ș�H؎�%�Za�)���X>uW�Tz�Nyo����s���FQƤ��$��*�&�LLXL)�1�" L��eO��ɟ�9=���:t��Z���c��Ž���Y?�ӭV�wv�~,Y��r�ۗ�|�y��GaF�����C�����.�+� ���v1���fήJ�����]�S��T��B��n5sW}y�$��~z�'�c ��8 ��� ,! �p��VN�S��N�N�q��y8z˱�A��4��*��'������2n<�s���^ǧ˭P�Jޮɏ�U�G�L�J�*#��<�V��t7�8����TĜ>��i}K%,���)[��z�21z ?�N�i�n1?T�I�R#��m-�����������������1����lA�`��fT5+��ܐ�c�q՝��ʐ��,���3�f2U�եmab��#ŠdQ�y>\��)�SLY����w#��.���ʑ�f��� ,"+�w�~�N�'�c�O�3F�������N<���)j��&��,-� �љ���֊�_�zS���TǦ����w�>��?�������n��U仆�V���e�����0���$�C�d���rP �m�׈e�Xm�Vu� �L��.�bֹ��� �[Դaզ���*��\y�8�Է:�Ez\�0�Kq�C b��̘��cө���Q��=0Y��s�N��S.���3.���O�o:���#���v7�[#߫ ��5�܎�L���Er4���9n��COWlG�^��0k�%<���ZB���aB_���������'=��{i�v�l�$�uC���mƎҝ{�c㱼�y]���W�i ��ߧc��m�H� m�"�"�����;Y�ߝ�Z�Ǔ�����:S#��|}�y�,/k�Ld� TA�(�AI$+I3��;Y*���Z��}|��ӧO��d�v��..#:n��f>�>���ȶI�TX��� 8��y����"d�R�|�)0���=���n4��6ⲑ�+��r<�O�܂~zh�z����7ܓ�HH�Ga롏���nCo�>������a ���~]���R���̲c?�6(�q�;5%� |�uj�~z8R=X��I�V=�|{v�Gj\gc��q����z�؋%M�ߍ����1y��#��@f^���^�>N�����#x#۹��6�Y~�?�dfPO��{��P�4��V��u1E1J �*|���%���JN��`eWu�zk M6���q t[�� ��g�G���v��WIG��u_ft����5�j�"�Y�:T��ɐ���*�;� e5���4����q$C��2d�}���� _S�L#m�Yp��O�.�C�;��c����Hi#֩%+) �Ӎ��ƲV���SYź��g |���tj��3�8���r|���V��1#;.SQ�A[���S������#���`n�+���$��$I �P\[�@�s��(�ED�z���P��])8�G#��0B��[ى��X�II�q<��9�~[Z멜�Z�⊔IWU&A>�P~�#��dp<�?����7���c��'~���5 ��+$���lx@�M�dm��n<=e�dyX��?{�|Aef ,|n3�<~z�ƃ�uۧ�����P��Y,�ӥQ�*g�#먙R�\���;T��i,��[9Qi歉����c>]9�� ��"�c��P�� �Md?٥��If�ت�u��k��/����F��9�c*9��Ǎ:�ØF���z�n*�@|I�ށ9����N3{'��[�'ͬ�Ҳ4��#}��!�V� Fu��,�,mTIk���v C�7v���B�6k�T9��1�*l� '~��ƞF��lU��'�M ����][ΩũJ_�{�i�I�n��$���L�� j��O�dx�����kza۪��#�E��Cl����x˘�o�����V���ɞ�ljr��)�/,�߬h�L��#��^��L�ф�,íMƁe�̩�NB�L�����iL����q�}��(��q��6IçJ$�W�E$��:������=#����(�K�B����zђ <��K(�N�۫K�w��^O{!����)�H���>x�������lx�?>Պ�+�>�W���,Ly!_�D���Ō�l���Q�!�[ �S����J��1��Ɛ�Y}��b,+�Lo�x�ɓ)����=�y�oh�@�꥟/��I��ѭ=��P�y9��� �ۍYӘ�e+�p�Jnϱ?V\SO%�(�t� ���=?MR�[Ș�����d�/ ��n�l��B�7j� ��!�;ӥ�/�[-���A�>�dN�sLj ��,ɪv��=1c�.SQ�O3�U���ƀ�ܽ�E����������̻��9G�ϷD�7(�}��Ävӌ\�y�_0[w ���<΍>����a_��[0+�L��F.�޺��f�>oN�T����q;���y\��bՃ��y�jH�<|q-eɏ�_?_9+P���Hp$�����[ux�K w�Mw��N�ی'$Y2�=��q���KB��P��~������Yul:�[<����F1�2�O���5=d����]Y�sw:���Ϯ���E��j,_Q��X��z`H1,#II ��d�wr��P˂@�ZJV����y$�\y�{}��^~���[:N����ߌ�U�������O��d�����ؾe��${p>G��3c���Ė�lʌ�� ת��[��`ϱ�-W����dg�I��ig2��� ��}s ��ؤ(%#sS@���~���3�X�nRG�~\jc3�v��ӍL��M[JB�T��s3}��j�Nʖ��W����;7��ç?=X�F=-�=����q�ߚ���#���='�c��7���ڑW�I(O+=:uxq�������������e2�zi+�kuG�R��������0�&e�n���iT^J����~\jy���p'dtG��s����O��3����9* �b#Ɋ�� p������[Bws�T�>d4�ۧs���nv�n���U���_�~,�v����ƜJ1��s�� �QIz��)�(lv8M���U=�;����56��G���s#�K���MP�=��LvyGd��}�VwWBF�'�à �?MH�U�g2�� ����!�p�7Q��j��ڴ����=��j�u��� Jn�A s���uM������e��Ɔ�Ҕ�!)'��8Ϣ�ٔ��ޝ(��Vp���צ֖d=�IC�J�Ǡ{q������kԭ�߸���i��@K����u�|�p=..�*+����x�����z[Aqġ#s2a�Ɗ���RR�)*HRsi�~�a &f��M��P����-K�L@��Z��Xy�'x�{}��Zm+���:�)�) IJ�-i�u���� ���ܒH��'�L(7�y�GӜq���� j��� 6ߌg1�g�o���,kر���tY�?W,���p���e���f�OQS��!K�۟cҒA�|ս�j�>��=⬒��˧L[�� �߿2JaB~R��u�:��Q�] �0H~���]�7��Ƽ�I���(}��cq '�ήET���q�?f�ab���ӥvr� �)o��-Q��_'����ᴎo��K������;��V���o��%���~OK ����*��b�f:���-ťIR��`B�5!RB@���ï�� �u �̯e\�_U�_������� g�ES��3�������QT��a����x����U<~�c?�*�#]�MW,[8O�a�x��]�1bC|踤�P��lw5V%�)�{t�<��d��5���0i�XSU��m:��Z�┵�i�"��1�^B�-��P�hJ��&)O��*�D��c�W��vM��)����}���P��ܗ-q����\mmζZ-l@�}��a��E�6��F�@��&Sg@���ݚ�M����� ȹ 4����#p�\H����dYDo�H���"��\��..R�B�H�z_�/5˘����6��KhJR��P�mƶi�m���3�,#c�co��q�a)*Pt����R�m�k�7x�D�E�\Y�閣_X�<���~�)���c[[�BP����6�Yq���S��0����%_����;��Àv�~�| VS؇ ��'O0��F0��\���U�-�d@�����7�SJ*z��3n��y��P����O���������m�~�P�3|Y��ʉr#�C�<�G~�.,! ���bqx���h~0=��!ǫ�jy����l�O,�[B��~��|9��ٱ����Xly�#�i�B��g%�S��������tˋ���e���ې��\[d�t)��.+u�|1 ������#�~Oj����hS�%��i.�~X���I�H�m��0n���c�1uE�q��cF�RF�o���7� �O�ꮧ� ���ۛ{��ʛi5�rw?׌#Qn�TW��~?y$��m\�\o����%W� ?=>S�N@�� �Ʈ���R����N�)�r"C�:��:����� �����#��qb��Y�. �6[��2K����2u�Ǧ�HYR��Q�MV��� �G�$��Q+.>�����nNH��q�^��� ����q��mM��V��D�+�-�#*�U�̒ ���p욳��u:�������IB���m���PV@O���r[b= �� ��1U�E��_Nm�yKbN�O���U�}�the�`�|6֮P>�\2�P�V���I�D�i�P�O;�9�r�mAHG�W�S]��J*�_�G��+kP�2����Ka�Z���H�'K�x�W�MZ%�O�YD�Rc+o��?�q��Ghm��d�S�oh�\�D�|:W������UA�Qc yT�q������~^�H��/��#p�CZ���T�I�1�ӏT����4��"�ČZ�����}��`w�#�*,ʹ�� ��0�i��課�Om�*�da��^gJ݅{���l�e9uF#T�ֲ��̲�ٞC"�q���ߍ ոޑ�o#�XZTp����@ o�8��(jd��xw�]�,f���`~�|,s��^����f�1���t��|��m�򸄭/ctr��5s��7�9Q�4�H1꠲BB@l9@���C�����+�wp�xu�£Yc�9��?`@#�o�mH�s2��)�=��2�.�l����jg�9$�Y�S�%*L������R�Y������7Z���,*=�䷘$�������arm�o�ϰ���UW.|�r�uf����IGw�t����Zwo��~5 ��YյhO+=8fF�)�W�7�L9lM�̘·Y���֘YLf�큹�pRF���99.A �"wz��=E\Z���'a� 2��Ǚ�#;�'}�G���*��l��^"q��+2FQ� hj��kŦ��${���ޮ-�T�٭cf�|�3#~�RJ����t��$b�(R��(����r���dx� >U b�&9,>���%E\� Ά�e�$��'�q't��*�א���ެ�b��-|d���SB�O�O��$�R+�H�)�܎�K��1m`;�J�2�Y~9��O�g8=vqD`K[�F)k�[���1m޼c��n���]s�k�z$@��)!I �x՝"v��9=�ZA=`Ɠi �:�E��)`7��vI��}d�YI�_ �o�:ob���o ���3Q��&D&�2=�� �Ά��;>�h����y.*ⅥS������Ӭ�+q&����j|UƧ����}���J0��WW< ۋS�)jQR�j���Ư��rN)�Gű�4Ѷ(�S)Ǣ�8��i��W52���No˓� ۍ%�5brOn�L�;�n��\G����=�^U�dI���8$�&���h��'���+�(������cȁ߫k�l��S^���cƗjԌE�ꭔ��gF���Ȓ��@���}O���*;e�v�WV���YJ\�]X'5��ղ�k�F��b 6R�o՜m��i N�i����>J����?��lPm�U��}>_Z&�KK��q�r��I�D�Չ~�q�3fL�:S�e>���E���-G���{L�6p�e,8��������QI��h��a�Xa��U�A'���ʂ���s�+טIjP�-��y�8ۈZ?J$��W�P� ��R�s�]��|�l(�ԓ��sƊi��o(��S0��Y� 8�T97.�����WiL��c�~�dxc�E|�2!�X�K�Ƙਫ਼�$((�6�~|d9u+�qd�^3�89��Y�6L�.I�����?���iI�q���9�)O/뚅����O���X��X�V��ZF[�یgQ�L��K1���RҖr@v�#��X�l��F���Нy�S�8�7�kF!A��sM���^rkp�jP�DyS$N���q��nxҍ!U�f�!eh�i�2�m���`�Y�I�9r�6� �TF���C}/�y�^���Η���5d�'��9A-��J��>{�_l+�`��A���[�'��յ�ϛ#w:݅�%��X�}�&�PSt�Q�"�-��\縵�/����$Ɨh�Xb�*�y��BS����;W�ջ_mc�����vt?2}1�;qS�d�d~u:2k5�2�R�~�z+|HE!)�Ǟl��7`��0�<�,�2*���Hl-��x�^����'_TV�gZA�'j� ^�2Ϊ��N7t�����?w�� �x1��f��Iz�C-Ȗ��K�^q�;���-W�DvT�7��8�Z�������� hK�(P:��Q- �8�n�Z���܃e貾�<�1�YT<�,�����"�6{/ �?�͟��|1�:�#g��W�>$����d��J��d�B��=��jf[��%rE^��il:��B���x���Sּ�1հ��,�=��*�7 fcG��#q� �eh?��2�7�����,�!7x��6�n�LC�4x��},Geǝ�tC.��vS �F�43��zz\��;QYC,6����~;RYS/6���|2���5���v��T��i����������mlv��������&� �nRh^ejR�LG�f���? �ۉҬܦƩ��|��Ȱ����>3����!v��i�ʯ�>�v��オ�X3e���_1z�Kȗ\<������!�8���V��]��?b�k41�Re��T�q��mz��TiOʦ�Z��Xq���L������q"+���2ۨ��8}�&N7XU7Ap�d�X��~�׿��&4e�o�F��� �H����O���č�c�� 懴�6���͉��+)��v;j��ݷ�� �UV�� i��� j���Y9GdÒJ1��詞�����V?h��l����l�cGs�ځ�������y�Ac�����\V3�? �� ܙg�>qH�S,�E�W�[�㺨�uch�⍸�O�}���a��>�q�6�n6����N6�q������N ! 1AQaq�0@����"2BRb�#Pr���3C`��Scst���$4D���%Td�� ?���N����a��3��m���C���w��������xA�m�q�m���m������$����4n淿t'��C"w��zU=D�\R+w�p+Y�T�&�պ@��ƃ��3ޯ?�Aﶂ��aŘ���@-�����Q�=���9D��ռ�ѻ@��M�V��P��܅�G5�f�Y<�u=,EC)�<�Fy'�"�&�չ�X~f��l�KԆV��?�� �W�N����=(� �;���{�r����ٌ�Y���h{�١������jW����P���Tc�����X�K�r��}���w�R��%��?���E��m�� �Y�q|����\lEE4���r���}�lsI�Y������f�$�=�d�yO����p�����yBj8jU�o�/�S��?�U��*������ˍ�0������u�q�m [�?f����a�� )Q�>����6#������� ?����0UQ����,IX���(6ڵ[�DI�MNލ�c&���υ�j\��X�R|,4��� j������T�hA�e��^���d���b<����n�� �즇�=!���3�^�`j�h�ȓr��jẕ�c�,ٞX����-����a�ﶔ���#�$��]w�O��Ӫ�1y%��L�Y<�wg#�ǝ�̗`�x�xa�t�w��»1���o7o5��>�m뭛C���Uƃߜ}�C���y1Xνm�F8�jI���]����H���ۺиE@I�i;r�8ӭ����V�F�Շ| ��&?�3|x�B�MuS�Ge�=Ӕ�#BE5G�����Y!z��_e��q�р/W>|-�Ci߇�t�1ޯќd�R3�u��g�=0 5��[?�#͏��q�cf���H��{ ?u�=?�?ǯ���}Z��z���hmΔ�BFTW�����<�q�(v� ��!��z���iW]*�J�V�z��gX֧A�q�&��/w���u�gYӘa���; �i=����g:��?2�dž6�ى�k�4�>�Pxs����}������G�9��3 ���)gG�R<>r h�$��'nc�h�P��Bj��J�ҧH� -��N1���N��?��~��}-q!=��_2hc�M��l�vY%UE�@|�v����M2�.Y[|y�"Eï��K�ZF,�ɯ?,q�?v�M 80jx�"�;�9vk�����+ ֧�� �ȺU��?�%�vcV��mA�6��Qg^M����A}�3�nl� QRN�l8�kkn�'�����(��M�7m9و�q���%ޟ���*h$Zk"��$�9��: �?U8�Sl��,,|ɒ��xH(ѷ����Gn�/Q�4�P��G�%��Ա8�N��!� �&�7�;���eKM7�4��9R/%����l�c>�x;������>��C�:�����t��h?aKX�bhe�ᜋ^�$�Iհ �hr7%F$�E��Fd���t��5���+�(M6�t����Ü�UU|zW�=a�Ts�Tg������dqP�Q����b'�m���1{|Y����X�N��b �P~��F^F:����k6�"�j!�� �I�r�`��1&�-$�Bevk:y���#yw��I0��x��=D�4��tU���P�ZH��ڠ底taP��6����b>�xa����Q�#� WeF��ŮNj�p�J* mQ�N����*I�-*�ȩ�F�g�3 �5��V�ʊ�ɮ�a��5F���O@{���NX��?����H�]3��1�Ri_u��������ѕ�� ����0��� F��~��:60�p�͈�S��qX#a�5>���`�o&+�<2�D����: �������ڝ�$�nP���*)�N�|y�Ej�F�5ټ�e���ihy�Z �>���k�bH�a�v��h�-#���!�Po=@k̆IEN��@��}Ll?j�O������߭�ʞ���Q|A07x���wt!xf���I2?Z��<ץ�T���cU�j��]��陎Ltl �}5�ϓ��$�,��O�mˊ�;�@O��jE��j(�ا,��LX���LO���Ц�90�O �.����a��nA���7������j4 ��W��_ٓ���zW�jcB������y՗+EM�)d���N�g6�y1_x��p�$Lv:��9�"z��p���ʙ$��^��JԼ*�ϭ����o���=x�Lj�6�J��u82�A�H�3$�ٕ@�=Vv�]�'�qEz�;I˼��)��=��ɯ���x �/�W(V���p�����$ �m�������u�����񶤑Oqˎ�T����r��㠚x�sr�GC��byp�G��1ߠ�w e�8�$⿄����/�M{*}��W�]˷.�CK\�ުx���/$�WPw���r� |i���&�}�{�X� �>��$-��l���?-z���g����lΆ���(F���h�vS*���b���߲ڡn,|)mrH[���a�3�ר�[1��3o_�U�3�TC�$��(�=�)0�kgP���� ��u�^=��4 �WYCҸ:��vQ�ר�X�à��tk�m,�t*��^�,�}D*� �"(�I��9R����>`�`��[~Q]�#af��i6l��8���6�:,s�s�N6�j"�A4���IuQ��6E,�GnH��zS�HO�uk�5$�I�4��ؤ�Q9�@��C����wp�BGv[]�u�Ov���0I4���\��y�����Q�Ѹ��~>Z��8�T��a��q�ޣ;z��a���/��S��I:�ܫ_�|������>=Z����8:�S��U�I�J��"IY���8%b8���H��:�QO�6�;7�I�S��J��ҌAά3��>c���E+&jf$eC+�z�;��V����� �r���ʺ������my�e���aQ�f&��6�ND��.:��NT�vm�<- u���ǝ\MvZY�N�NT��-A�>jr!S��n�O 1�3�Ns�%�3D@���`������ܟ 1�^c<���� �a�ɽ�̲�Xë#�w�|y�cW�=�9I*H8�p�^(4���՗�k��arOcW�tO�\�ƍR��8����'�K���I�Q�����?5�>[�}��yU�ײ -h��=��% q�ThG�2�)���"ו3]�!kB��*p�FDl�A���,�eEi�H�f�Ps�����5�H:�Փ~�H�0Dت�D�I����h�F3�������c��2���E��9�H��5�zԑ�ʚ�i�X�=:m�xg�hd(�v����׊�9iS��O��d@0ڽ���:�p�5�h-��t�&���X�q�ӕ,��ie�|���7A�2���O%P��E��htj��Y1��w�Ѓ!����  ���� ࢽ��My�7�\�a�@�ţ�J �4�Ȼ�F�@o�̒?4�wx��)��]�P��~�����u�����5�����7X ��9��^ܩ�U;Iꭆ 5 �������eK2�7(�{|��Y׎ �V��\"���Z�1� Z�����}��(�Ǝ"�1S���_�vE30>���p;� ΝD��%x�W�?W?v����o�^V�i�d��r[��/&>�~`�9Wh��y�;���R��� ;;ɮT��?����r$�g1�K����A��C��c��K��l:�'��3 c�ﳯ*"t8�~l��)���m��+U,z��`(�>yJ�?����h>��]��v��ЍG*�{`��;y]��I�T� ;c��NU�fo¾h���/$���|NS���1�S�"�H��V���T���4��uhǜ�]�v;���5�͠x��'C\�SBpl���h}�N����� A�Bx���%��ޭ�l��/����T��w�ʽ]D�=����K���ž�r㻠l4�S�O?=�k �M:� ��c�C�a�#ha���)�ѐxc�s���gP�iG��{+���x���Q���I= �� z��ԫ+ �8"�k�ñ�j=|����c ��y��CF��/��*9ж�h{ �?4�o� ��k�m�Q�N�x��;�Y��4膚�a�w?�6�>e]�����Q�r�:����g�,i"�����ԩA�*M�<�G��b�if��l^M��5� �Ҩ�{����6J��ZJ�����P�*�����Y���ݛu�_4�9�I8�7���������,^ToR���m4�H��?�N�S�ѕw��/S��甍�@�9H�S�T��t�ƻ���ʒU��*{Xs�@����f�����֒Li�K{H�w^���������Ϥm�tq���s� ���ք��f:��o~s��g�r��ט� �S�ѱC�e]�x���a��) ���(b-$(�j>�7q�B?ӕ�F��hV25r[7 Y� }L�R��}����*sg+��x�r�2�U=�*'WS��ZDW]�WǞ�<��叓���{�$�9Ou4��y�90-�1�'*D`�c�^o?(�9��u���ݐ��'PI&� f�Jݮ�������:wS����jfP1F:X �H�9dԯ���˝[�_54 �}*;@�ܨ�� ð�yn�T���?�ןd�#���4rG�ͨ��H�1�|-#���Mr�S3��G�3�����)�.᧏3v�z֑��r����$G"�`j �1t��x0<Ɔ�Wh6�y�6��,œ�Ga��gA����y��b��)��h�D��ß�_�m��ü �gG;��e�v��ݝ�nQ� ��C����-�*��o���y�a��M��I�>�<���]obD��"�:���G�A��-\%LT�8���c�)��+y76���o�Q�#*{�(F�⽕�y����=���rW�\p���۩�c���A���^e6��K������ʐ�cVf5$�'->���ՉN"���F�"�UQ@�f��Gb~��#�&�M=��8�ט�JNu9��D��[̤�s�o�~������ G��9T�tW^g5y$b��Y'��س�Ǵ�=��U-2 #�MC�t(�i� �lj�@Q 5�̣i�*�O����s�x�K�f��}\��M{E�V�{�υ��Ƈ�����);�H����I��fe�Lȣr�2��>��W�I�Ȃ6������i��k�� �5�YOxȺ����>��Y�f5'��|��H+��98pj�n�.O�y�������jY��~��i�w'������l�;�s�2��Y��:'lg�ꥴ)o#'Sa�a�K��Z� �m��}�`169�n���"���x��I ��*+� }F<��cГ���F�P�������ֹ*�PqX�x۩��,� ��N�� �4<-����%����:��7����W���u�`����� $�?�I��&����o��o��`v�>��P��"��l���4��5'�Z�gE���8���?��[�X�7(��.Q�-��*���ތL@̲����v��.5���[��=�t\+�CNܛ��,g�SQnH����}*F�G16���&:�t��4ُ"A��̣��$�b �|����#rs��a�����T�� ]�<�j��BS�('$�ɻ� �wP;�/�n��?�ݜ��x�F��yUn�~mL*-�������Xf�wd^�a�}��f�,=t�׵i�.2/wpN�Ep8�OР���•��R�FJ� 55TZ��T �ɭ�<��]��/�0�r�@�f��V��V����Nz�G��^���7hZi����k��3�,kN�e|�vg�1{9]_i��X5y7� 8e]�U����'�-2,���e"����]ot�I��Y_��n�(JҼ��1�O ]bXc���Nu�No��pS���Q_���_�?i�~�x h5d'�(qw52] ��'ޤ�q��o1�R!���`ywy�A4u���h<קy���\[~�4�\ X�Wt/� 6�����n�F�a8��f���z �3$�t(���q��q�x��^�XWeN'p<-v�!�{�(>ӽDP7��ո0�y)�e$ٕv�Ih'Q�EA�m*�H��RI��=:��� ���4牢) �%_iN�ݧ�l]� �Nt���G��H�L��� ɱ�g<���1V�,�J~�ٹ�"K��Q�� 9�HS�9�?@��k����r�;we݁�]I�!{ �@�G�[�"��`���J:�n]�{�cA�E����V��ʆ���#��U9�6����j�#Y�m\��q�e4h�B�7��C�������d<�?J����1g:ٳ���=Y���D�p�ц� ׈ǔ��1�]26؜oS�'��9�V�FVu�P�h�9�xc�oq�X��p�o�5��Ա5$�9W�V(�[Ak�aY錎qf;�'�[�|���b�6�Ck��)��#a#a˙��8���=äh�4��2��C��4tm^ �n'c���]GQ$[Wҿ��i���vN�{Fu ��1�gx��1┷���N�m��{j-,��x�� Ūm�ЧS�[�s���Gna���䑴�� x�p 8<������97�Q���ϴ�v�aϚG��Rt�Һ׈�f^\r��WH�JU�7Z���y)�vg=����n��4�_)y��D'y�6�]�c�5̪�\� �PF�k����&�c;��cq�$~T�7j ���nç]�<�g ":�to�t}�159�<�/�8������m�b�K#g'I'.W�����6��I/��>v��\�MN��g���m�A�yQL�4u�Lj�j9��#44�t��l^�}L����n��R��!��t��±]��r��h6ٍ>�yҏ�N��fU�� ���� Fm@�8}�/u��jb9������he:A�y�ծw��GpΧh�5����l}�3p468��)U��d��c����;Us/�֔�YX�1�O2��uq�s��`hwg�r~�{ R��mhN��؎*q 42�*th��>�#���E����#��Hv�O����q�}�����6�e��\�,Wk�#���X��b>��p}�դ��3���T5��†��6��[��@�P�y*n��|'f�֧>�lư΂�̺����SU�'*�q�p�_S�����M�� '��c�6�����m�� ySʨ;M��r���Ƌ�m�Kxo,���Gm�P��A�G�:��i��w�9�}M(�^�V��$ǒ�ѽ�9���|���� �a����J�SQ�a���r�B;����}���ٻ֢�2�%U���c�#�g���N�a�ݕ�'�v�[�OY'��3L�3�;,p�]@�S��{ls��X�'���c�jw�k'a�.��}�}&�� �dP�*�bK=ɍ!����;3n�gΊU�ߴmt�'*{,=SzfD� A��ko~�G�aoq�_mi}#�m�������P�Xhύ����mxǍ�΂���巿zf��Q���c���|kc�����?���W��Y�$���_Lv����l߶��c���`?����l�j�ݲˏ!V��6����U�Ђ(A���4y)H���p�Z_�x��>���e��R��$�/�`^'3qˏ�-&Q�=?��CFVR �D�fV�9��{�8g�������n�h�(P"��6�[�D���< E�����~0<@�`�G�6����Hг�cc�� �c�K.5��D��d�B���`?�XQ��2��ٿyqo&+�1^� DW�0�ꊩ���G�#��Q�nL3��c���������/��x ��1�1[y�x�პCW��C�c�UĨ80�m�e�4.{�m��u���I=��f�����0QRls9���f���������9���~f�����Ǩ��a�"@�8���ȁ�Q����#c�ic������G��$���G���r/$W�(��W���V�"��m�7�[m�A�m����bo��D� j����۳� l���^�k�h׽����� ��#� iXn�v��eT�k�a�^Y�4�BN��ĕ��0 !01@Q"2AaPq3BR������?���@4�Q�����T3,���㺠�W�[=JK�Ϟ���2�r^7��vc�:�9 �E�ߴ�w�S#d���Ix��u��:��Hp��9E!�� V 2;73|F��9Y���*ʬ�F��D����u&���y؟��^EA��A��(ɩ���^��GV:ݜDy�`��Jr29ܾ�㝉��[���E;Fzx��YG��U�e�Y�C���� ����v-tx����I�sם�Ę�q��Eb�+P\ :>�i�C'�;�����k|z�رn�y]�#ǿb��Q��������w�����(�r|ӹs��[�D��2v-%��@;�8<a���[\o[ϧw��I!��*0�krs)�[�J9^��ʜ��p1)� "��/_>��o��<1����A�E�y^�C��`�x1'ܣn�p��s`l���fQ��):�l����b>�Me�jH^?�kl3(�z:���1ŠK&?Q�~�{�ٺ�h�y���/�[��V�|6��}�KbX����mn[-��7�5q�94�������dm���c^���h� X��5��<�eޘ>G���-�}�دB�ޟ� ��|�rt�M��V+�]�c?�-#ڛ��^ǂ}���Lkr���O��u�>�-D�ry� D?:ޞ�U��ǜ�7�V��?瓮�"�#���r��չģVR;�n���/_� ؉v�ݶe5d�b9��/O��009�G���5n�W����JpA�*�r9�>�1��.[t���s�F���nQ� V 77R�]�ɫ8����_0<՜�IF�u(v��4��F�k�3��E)��N:��yڮe��P�`�1}�$WS��J�SQ�N�j�ٺ��޵�#l���ј(�5=��5�lǏmoW�v-�1����v,W�mn��߀$x�<����v�j(����c]��@#��1������Ǔ���o'��u+����;G�#�޸��v-lη��/(`i⣍Pm^���ԯ̾9Z��F��������n��1��� ��]�[��)�'������:�֪�W��FC����� �B9،!?���]��V��A�Վ�M��b�w��G F>_DȬ0¤�#�QR�[V��kz���m�w�"��9ZG�7'[��=�Q����j8R?�zf�\a�=��O�U����*oB�A�|G���2�54 �p��.w7� �� ��&������ξxGHp� B%��$g�����t�Џ򤵍z���HN�u�Я�-�'4��0��;_��3 !01"@AQa2Pq#3BR������?��ʩca��en��^��8���<�u#��m*08r��y�N"�<�Ѳ0��@\�p��� �����Kv�D��J8�Fҽ� �f�Y��-m�ybX�NP����}�!*8t(�OqѢ��Q�wW�K��ZD��Δ^e��!� ��B�K��p~�����e*l}z#9ң�k���q#�Ft�o��S�R����-�w�!�S���Ӥß|M�l޶V��!eˈ�8Y���c�ЮM2��tk���� ������J�fS����Ö*i/2�����n]�k�\���|4yX�8��U�P.���Ы[���l��@"�t�<������5�lF���vU�����W��W��;�b�cД^6[#7@vU�xgZv��F�6��Q,K�v��� �+Ъ��n��Ǣ��Ft���8��0��c�@�!�Zq s�v�t�;#](B��-�nῃ~���3g������5�J�%���O������n�kB�ĺ�.r��+���#�N$?�q�/�s�6��p��a����a��J/��M�8��6�ܰ"�*������ɗud"\w���aT(����[��F��U՛����RT�b���n�*��6���O��SJ�.�ij<�v�MT��R\c��5l�sZB>F��<7�;EA��{��E���Ö��1U/�#��d1�a�n.1ě����0�ʾR�h��|�R��Ao�3�m3 ��%�� ���28Q� ��y��φ���H�To�7�lW>����#i`�q���c����a��� �m,B�-j����݋�'mR1Ήt�>��V��p���s�0IbI�C.���1R�ea�����]H�6����������4B>��o��](��$B���m�����a�!=��?�B� K�Ǿ+�Ծ"�n���K��*��+��[T#�{E�J�S����Q�����s�5�:�U�\wĐ�f�3����܆&�)����I���Ԇw��E T�lrTf6Q|R�h:��[K�� �z��c֧�G�C��%\��_�a�84��HcO�bi��ؖV��7H �)*ģK~Xhչ0��4?�0��� �E<���}3���#���u�?�� ��|g�S�6ꊤ�|�I#Hڛ� �ա��w�X��9��7���Ŀ%�SL��y6č��|�F�a 8���b��$�sק�h���b9RAu7�˨p�Č�_\*w��묦��F ����4D~�f����|(�"m���NK��i�S�>�$d7SlA��/�²����SL��|6N�}���S�˯���g��]6��; �#�.��<���q'Q�1|KQ$�����񛩶"�$r�b:���N8�w@��8$�� �AjfG|~�9F ���Y��ʺ��Bwؒ������M:I岎�G��`s�YV5����6��A �b:�W���G�q%l�����F��H���7�������Fsv7��k�� 403WebShell
403Webshell
Server IP : 104.21.45.146  /  Your IP : 172.69.214.108
Web Server : Apache/2.4.52 (Ubuntu)
System : Linux ip-172-31-19-221 6.8.0-1029-aws #31~22.04.1-Ubuntu SMP Thu Apr 24 21:16:18 UTC 2025 x86_64
User : www-data ( 33)
PHP Version : 8.1.28
Disable Function : NONE
MySQL : OFF  |  cURL : ON  |  WGET : ON  |  Perl : ON  |  Python : OFF  |  Sudo : ON  |  Pkexec : ON
Directory :  /efsdata/scitechnol.com/httpdocs/submission/uploads/

Upload File :
current_dir [ Writeable ] document_root [ Writeable ]

 

Command :


[ Back ]     

Current File : /efsdata/scitechnol.com/httpdocs/submission/uploads/1767-0-Manuscript-2014-03-28.doc
��ࡱ�>��	������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������	��'rbjbjW�W�	h�5�5��iM�������dd�$�$�$�$�$$�����$�$�$P%To%T�$Q72�%��'�'�'�'�(,�(�(�6�6�6�6�6�6�6$�:�%=L�6�$�(�(�(�(�(�6�$�$�'�'�7�1�1�1�(��$�'�$�'�6�1�(�6�1�1:6,P6�'����pd�J��$�/".6�6!70Q7F6
q=�/�q=P6P6q=�$d6X�1�(�(�(�6�6�1�(�(�(Q7�(�(�(�(��������������������������������������������������������������������q=�(�(�(�(�(�(�(�(�(d	m#:	
Cumulative Radiation Exposure in 

Liver Transplant Candidates and Patients 

Transplanted with Hepatocellular Carcinoma


Sammy Saab1,2, Vignan Manne2, Vincent Bui2, Vinay Sundaram3

Departments of Medicine1 and Surgery,2 at the University of California at Los Angeles, Department of Medicine, Cedars-Sinai Medical Center


Role in the Study: Study concept and design (SS); acquisition of data (VM, VB); analysis and interpretation of data (SS, VM, VB, VS); drafting of the manuscript (SS, VM, VB); critical revision of the manuscript for important intellectual content (SS, VM, VS); statistical analysis (VM, VB); obtained funding (not applicable); administrative, technical, or material support; study supervision (SS)


Conflicts: All authors have no conflicts of interest

Running Title: Radiation exposure

Key Words: Radiation, Cirrhosis, Liver Transplantation


Sammy Saab, MD, MPH, AGAF
Pfleger Liver Institute
UCLA Medical Center
200 Medical Plaza, Suite 214
Los Angeles, CA 90095
310-206-6705 (V)
310-206-4197 (F)
SSaab@mednet.ucla.eduAbbreviations
HCC- Hepatocellular Carcinoma
CT- Computed Tomography
MRI- Magnetic Resonance Imaging
LAR- Lifetime Attributable Risk
AASLD- American Association for the Study of Liver Diseases
UNOS- United Network for Organ Sharing
OPTN- Organ Procurement and Transplant Network
SRTR- Scientific Registry of Transplant Recipients
MELD- Model for End-stage Liver Disease
mSv- milliSeiverts
SD- Standard Deviation Abstract
Background
Liver transplant candidates and recipients undergo regular imaging for hepatocellular carcinoma (HCC) screening and surveillance.  Excessive radiation exposure is associated with risks of malignancy and infection.  Longitudinal studies on the amount and impact of radiation exposure in patients with liver disease are lacking.
Aim
We calculated the mean time wait list for liver transplantation, for patients with and without HCC using data from the Scientific Registry of Transplant Recipients.
Methods
We estimated the radiation exposure in three different populations: liver transplant candidates without cancer, liver transplant candidates followed for liver cancer, and patients transplanted for liver cancer.  Three HCC screening strategies were also compared in patients waiting for liver transplantation.  Sensitivity analyses were performed for radiation exposure. 
Results
Using baseline values, the mean radiation exposure for patients being screened for HCC using ultrasounds every 6 months, alternating between ultrasound and CT every 6 months, or CT every 6 months was 10, 27 and 35 mSv.  For transplant candidates undergoing surveillance for recurrent HCC, the mean radiation exposure was 36 mSv and 15 mSv from abdominal and chest CT scans respectively.  In liver transplant recipients, the cumulative radiation exposure 5 years after liver transplantation was 144 mSv.
Conclusion
Longitudinal studies are needed to assess the safety and long term impact of radiation exposure.  Patients transplanted with HCC represent a particularly high risk group for potential complications.
Introduction
	The incidence of hepatocellular carcinoma (HCC) continues to increase in the United States and Europe1-3.  In fact, HCC is one of the fastest growing cancers in world. Abdominal ultrasound serves as the basis for HCC screening in patients at risk of developing cancer4,5.  From a pharmacoeconomic basis, ultrasounds have been demonstrated to be a cost-effective modality in screening for HCC in patients with cirrhosis6,7.
Accurate diagnosis and characterization of HCC is essential since method of treatment and candidacy for transplant listing depend tumor burden8. Further imaging with Computed Tomography (CT) scans and Magnetic Resonance Imaging (MRI) are used to confirm a diagnosis of HCC, assess for local and distant metastatic disease, and identify vascular invasion 9.  Computed Tomography scans are often preferred over MRI�s for HCC screening and surveillance, due to greater availability and lower costs.  Unlike MRI, there is a radiation dose associated with CT scans.  The impact of radiation exposure from CT scans in patients with chronic liver disease is unknown.   Not only is there is a paucity of data on the cumulative radiation threshold responsible to cause damage in patients with advanced liver disease there is also no commonly accepted tracking system to monitor radiation exposure.  
Excessive radiation exposure is a well known cause effects such as dermatitis and malignancy10-12. Less than one percent of all cancers in the US may be attributable to the radiation from CT studies in 1991-199613,14. However, the estimation is now believed higher in the range of 1.5-2.0% after adjusting for current CT use12.  Accumulation of radiation lasts per lifetime, and is measured by LAR (Lifetime Attributable Risk), with each dosage increasing LAR12.  
Understanding the potential harm for radiation is essential. Currently, there are approximately 15,000 patients waiting for liver transplantation in the United States15.  These patients undergo screening and surveillance for liver cancer, and likely exposed to varied amounts of radiation from CT scans.  There are also over 60,000 liver transplant recipients being followed15.  After liver transplantation, recipients who had HCC undergo subsequent imaging testing to assess for recurrent HCC disease.  Because of the lack of a commonly accepted tracking system to monitor radiation exposure and the lack of published longitudinal studies on radiation exposure in patients with cirrhosis and liver transplant recipients, we performed the current analysis to estimate radiation exposure in liver transplant candidates and recipients.  
Methods
Screening and Surveillance Strategies
We compared three screening strategies for hepatocellular carcinoma in patients on the liver transplant list: A) The first strategy followed the AASLD guidelines with abdominal ultrasound every 6 months4,5; B) The second strategy consisted of alternating abdominal ultrasound and non-ultrasound imaging every 6 months; and C).  The third screening strategy consisted of CT scan imaging every 6months.  We assumed 100% adherence with screening strategies before and after liver transplantation.   We varied the proportion of patients underwent triple phase, as compared to dual phase CT in a sensitivity analysis.  We further assumed there was no radiation exposure with abdominal ultrasounds.  All patients were assumed to undergo a dual phase CT scan as a baseline for liver transplant evaluation.
	As there are no guidelines regarding surveillance in patients with HCC listed for transplantation or post-transplantation, the frequency and mode of imaging may vary among institutions16.  For our model, we also surveyed transplant hepatologists in the Los Angeles area (University of California Los Angeles, Cedars-Sinai Medical Center, University of Southern California, Loma Linda).  These centers had over 1300 patients on their transplant list by the end of 201117.

Liver Transplant Wait Time
Wait list data was obtained from the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database18. A query had been sent to UNOS for a Standard Analysis and Research file (STAR), which was then mailed and received by us on 10/31/2012. A dataset of 41,018 patients was created, of subjects age 18 or older, who underwent primary liver transplantation from January 2002 through July 2012. Patients who underwent living donor transplantation, repeat transplantation or multi-organ transplantation were excluded. 
We looked at the mean wait time for liver transplantation across 4 different MELD score classifications: <10, 11-18, 19-24, and >24.  We calculated the mean time wait list with standard deviation for patients waiting for liver transplantation.  The standard deviation for each MELD score included the range for all regions.  Thus, we used an adjusted value for wait time was the arithmetic addition of the mean with one standard deviation.  A separate analysis was performed for patients awaiting liver transplantation with a diagnosis of hepatocellular carcinoma.  

Radiation Exposure
	Different types of CT scans expose patients to differing amounts of radiation.  Previous studies indicate that a typical radiation dose differs based on the machine being used and the parameters set but generally varies from 15-30 milliSeiverts (mSv) per scan.12 We used a conservative dose value of 10 mSv and varied the dose value in a sensitivity analysis 1.5 and 2 times the baseline dose (Table 1).  We also used a baseline value of 20 mSv for triple phase CT scan and 7 mSv for chest CT, and varied the values in a sensitivity analysis 1.5 and 2 times the baseline dose.  We varied the percentage of triple phase CT scans utilized. Under baseline conditions, 90% of abdominal CT scans were dual phase and 10% were triple phase.  The use of Magnetic Resonance Imaging (MRI) was not included in the model because of the varied accessibility in clinical practice.

Results
Pretransplant without cancer
Radiation exposure varied according to the HCC screening strategy. The mean (� SD) wait time in the United States was 174 (� 334) days.  In Strategy 1, the expected radiation exposure was 10 mSv.  In this strategy, an abdominal CT scan was only performed during the transplant evaluation.   As anticipated, radiation exposure was greater in Strategies 2 and 3.  Most transplant hepatologists followed Strategy 2 (alternating between ultrasound and CT every 6 months) (Table 2).  Using baseline radiation doses, the cumulative mean (� SD) radiation exposure in Strategy 2 was 27 (� 35) mSv.   
If the radiation dose from the scans increased to 2 times their baseline values (chest CT 14 mSv, abdominal dual phase CT 20 mSv, abdominal triple phase CT 30 mSv), then the mean radiation exposure would became 53 (�69) mSv.  If the proportion of triple phase utilized increased from 20% to 40% and 80%, then the cumulative radiation exposure increased to 56 (�73) mSv and 62 (�81) mSv, respectively.  
Under strategy 3, the mean (� SD) cumulative radiation exposure was 35 (�51) mSv using baseline dose assumptions.   The mean cumulative radiation exposure according to MELD score varied from 32 to 41mSv.  If the CT scan radiation dose increased to 2x the baseline value of 10 mSv for dual phase CT, then the mean (� SD) cumulative radiation exposure increased to 71 (� 103) mSv.  When the proportion of triple phase CT was varied to 40% and 80% with a radiation dose using baseline radiation dose doses, the mean (� SD) cumulative radiation exposure was 37 (� 54) mSv and 41 (� 60).

Pretransplant with hepatocellular cancer
Most transplant hepatologists agreed that a baseline abdominal and chest CT scan be performed at the time a HCC diagnosis is suspected based on findings on an ultrasound.  After the tumor has been treated, patients are surveyed for recurrent HCC.  However, there is variability on how patients are followed16.  The most frequent strategy for tumor recurrence surveillance was abdominal CT was performed every three months, and a chest CT repeated twice a year among transplant hepatologist in Southern California (Table 3).  All transplant hepatologist recommended triple rather than dual phase CT scan.  For the model, however, we assumed 20% abdominal CT were triple phase and varied the likelihood of triple phase up to 80%.  The mean (� SD) wait for liver transplantation in patients with a diagnosis of HCC is 204 (� 334) days in the United States.  
The mean (�SD) total cumulative radiation exposure was 51 (� 72) mSv.  The total cumulative radiation exposure from abdominal imaging was 36 mSv vs 15 mSv from chest CT using baseline assumptions.   The total mean (�SD) cumulative exposure increased to 102 (� 144) mSv if the radiation dose was increased 2x over baseline.  If the proportion of triple phase CT was changed to 40% of abdominal CT utilized, the mean (�SD) cumulative exposure was 54 (� 77) mSv using baseline assumptions, but 108 (�153) mSv if the radiation dose was also increased to 2x over baseline. 

Post transplant with cancer
The cumulative radiation exposure was calculated according to institutional protocol for recurrent hepatocellular carcinoma surveillance after 5 years (Table 4).  Institution 4 varied their surveillance according to whether the recipient tumor burden was within Milan criteria19.  If the radiation doses were increased by 1.5 times the baseline, the exposure varied from 170 mSv to 320 mSv.  If the radiation were also increased to 2 times the baseline, the radiation exposure then increased to 222 mSV to 458 mSv.  In particular, radiation exposure was 67% greater in recipients whose tumor burden was beyond Milan criteria for Institution 4.  

Discussion
Abdominal imaging is an integral part of the management of patients with chronic liver disease.  Abdominal CT scans, in particular, are important for screening and diagnosing hepatocellular carcinoma, and assessing hepatic vasculature for transplant feasibility.  Patients who have been treated for HCC, are surveyed for recurrence with imaging on a regular basis.  After transplantation, recipients continue close imaging scrutiny with abdominal imaging.  The results of our analysis indicate that transplant recipients can be exposed to substantial amounts of radiation.  
We compared three different strategies for HCC screening in patients at risk of cancer.  The first strategy followed AASLD guidelines, and was associated with the lowest radiation cumulative exposure.  The second and third strategies followed most of the transplant hepatologist in the greater Los Angeles performed among patients who are obese.  The reasoning behind the strategies is that ultrasound may be less accurate in HCC screening in obese patients with nodular liver20,21.  However, CT scans have not been routinely evaluated for HCC screening purposes21,22. Overall, the exposure varied from 10 mSv in a patient who is screened for HCC with biannual ultrasound, to 34 mSV to a patient who is screened with abdominal CT scans every 6 months.   
As previously noted by Hyder et al, we also found variability in the surveillance of patients treated for HCC16.  In our survey, providers performed abdominal imaging surveillance every X to Y months while waiting for transplant in a patient who has been treated for HCC.  After liver transplantation, the frequency of abdominal and chest surveillance also varied, as well as the length of time surveillance is performed.  The cumulative radiation exposure becomes substantial who are being surveyed for HCC recurrence, either pre or post transplantation.  The total cumulative radiation exposure in a patient who was transplanted for known HCC can be as be approximately 200 mSv 5 years after liver transplantation.  
Excessive radiation exposure is known to cause damage to cellular DNA with increasing exposure leading to increasing risk of damage12. The damage done by radiation exposure due to CT scans is difficult to measure because individual CT scans do not yield very high levels of radiation, the ionizing radiation of X-rays are stochastic in nature, and the time course between cause and effect tends to generally be measured over extended periods of time23. The amount of radiation that is associated with damage varies according to whether the exposure is from single or from cumulative setting, body habitus, site of exposure, and age of patient24.  For instance, the estimated life time attributable risk (LAR) of developing a solid cancer or leukemia from a single dose of 10 mSv is 1 in 1000, but 1 in 100 with a single dose of 100 mSv exposure23.   Although the radiation exposure doses may be higher for head scans, the risks are believed to be higher for abdominal scans because the digestive organs are more sensitive than the brain to radiation-induced cancer12.  Young people appear to more sensitive to the radiation exposure induced damage because they are believe to be more radiosensitive25. Pediatric doses are much higher than adult doses because a child�s thinner torso provides less shielding of organs from radiation exposure.
There are several limitations to our study.  First, unlike a decision analysis model or cost-effective study, we did not create a hypothetical cohort to follow.  We thought presenting our data in tabular form under different scenarios would be more descriptive and informative.  In real life, patients may transition between been screened for liver cancer to being surveyed for recurrent HCC.  Thus, our model may underestimate radiation exposure.  Patients who develop cancer would have the additive radiation exposure from screening period.  Another limitation is the radiation exposure may difficult to ascertain.  Indeed, most studies present radiation exposure as a range and the intensity of exposure may vary according to age of patient and comorbities. Nevertheless, we varied in our model the amount of radiation exposure, and to the use of triple phase CT scans which is associated with greater radiation to help generalize our results. Another limitation is that our model specifically assessed for radiation exposure in the context of screening and surveillance of HCC.  Patients with cirrhosis are likely to undergo additional abdominal imaging such as for investigation of abdominal pain.  Thus, our model may also underestimate radiation exposure.
With increasing number of transplant recipients living, it is important to assess for factors that affect long term survival and quality of life.  CT imaging plays a critical role in the care of both liver transplant candidates and recipients.  However, long term impact of cumulative radiation exposure is largely unknown.  The results of our analysis highlight the need for further evaluation and study. 
Acknowledgement
The authors would like to thank the Southern California Transplant Hepatologists who participated in the survey. This work was based on Organ Procurement and Transplantation Network data from July 31, 2012 and supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. 

References
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Capocaccia R%5BAuthor%5D&cauthor=true&cauthor_uid=17555459"Capocaccia R,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Sant M%5BAuthor%5D&cauthor=true&cauthor_uid=17555459"Sant M,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Berrino F%5BAuthor%5D&cauthor=true&cauthor_uid=17555459"Berrino F,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Simonetti A%5BAuthor%5D&cauthor=true&cauthor_uid=17555459"Simonetti A,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Santi V%5BAuthor%5D&cauthor=true&cauthor_uid=17555459"Santi V,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Trevisani F%5BAuthor%5D&cauthor=true&cauthor_uid=17555459"Trevisani F;  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=EUROCARE Working Group%5BCorporate Author%5D"EUROCARE Working Group. Hepatocellular carcinoma: trends of incidence and survival in Europe and the United States at the end of the 20th century.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=sant+m%2C+santi+v"Am J Gastroenterol. 2007;102:1661-7. 
Altekruse SF, McGlynn KA, Reichman ME.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/19224838"Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.  J Clin Oncol. 2009;27:1485-91.
El-Serag HB, Davila JA, Petersen NJ, McGlynn KA.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/14623619"The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update.  Ann Intern Med. 2003;139:817-23. 
Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421�30. 
Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208�36. 
Saab S, Ly D, Nieto J, Kanwal F, Lu D, Raman S, Amado R, Nuesse B, Durazo F, Han S, Farmer DG, Ghobrial RM, Yersiz H, Chen P, Schwegel K, Goldstein LI, Tong M, Busuttil RW.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/12827551"Hepatocellular carcinoma screening in patients waiting for liver transplantation: a decision analytic model. Liver Transpl. 2003;9:672-81.
Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, Jackson S, Ryder S, Price A, Stein K.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/17767898"Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol Assess. 2007;11:1-206. 
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Llovet JM%5BAuthor%5D&cauthor=true&cauthor_uid=14667750"Llovet JM,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Burroughs A%5BAuthor%5D&cauthor=true&cauthor_uid=14667750"Burroughs A,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Bruix J%5BAuthor%5D&cauthor=true&cauthor_uid=14667750"Bruix J.Hepatocellular carcinoma.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/14667750"Lancet. 2003;362:1907-17. 
Sherman M.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/20203642"The radiological diagnosis of hepatocellular carcinoma. Am J Gastroenterol. 2010;105:610-2.
Berrington de Gonzalez A, Mahesh M, Kim KP, et al. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med.2009;169:2071-2077.  
Linet MS, Slovis TL, Miller DL, Kleinerman R, Lee C, Rajaraman P, Berrington De Gonzalez A. Cancer risks associated with external radiation from diagnostic imaging procedures. CA Cancer J Clin, 2012; doi 10.3322/caac. 21132. 
Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med. 2007;357:2277-84 
Sources and effects of ionizing radiation: United Nations Scientific Committee on the effects of atomic radiation: UNSCEAR 2000 report to the General Assembly. New York: United Nations, 2000. 
Berrington De Gonzalez A, Darby S. Risk of Cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet, 2004;363:345-51. 
Kim WR, Stock PG, Smith JM, Heimbach JK, Skeans MA, Edwards EB, Harper AM, Snyder JJ, Israni AK, Kasiske BL.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/23237697"OPTN/SRTR 2011 Annual Data Report: liver. Am J Transplant. 2013;13 Suppl 1:73-102
Hyder O, Dodson RM, Weiss M, Cosgrove DP, Herman JM, Geschwind JF, Kamel IR, Pawlik TM.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/23943387"Trends and Patterns of Utilization in Post-treatment Surveillance Imaging Among Patients Treated for Hepatocellular Carcinoma. J Gastrointest Surg. 2013 in press.
Scientific Registry of Transplant Recipients.  HYPERLINK "http://www.srtr.org/"http://www.srtr.org.  Accessed August 27, 2013.
Organ Sharing/Organ Procurement and Transplantation Network.  HYPERLINK "http://Www.unos.org/"www.unos.org. Accessed August 31, 2013.
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, et al. Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis. N Engl J Med 1996; 334:693-700.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=El-Serag HB%5BAuthor%5D&cauthor=true&cauthor_uid=21317990"El-Serag HB,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Davila JA%5BAuthor%5D&cauthor=true&cauthor_uid=21317990"Davila JA. Surveillance for hepatocellular carcinoma: in whom and how?  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/21317990"Therap Adv Gastroenterol. 2011;4:5-10. 
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Tong MJ%5BAuthor%5D&cauthor=true&cauthor_uid=11350553"Tong MJ,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Blatt LM%5BAuthor%5D&cauthor=true&cauthor_uid=11350553"Blatt LM,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Kao VW%5BAuthor%5D&cauthor=true&cauthor_uid=11350553"Kao VW. Surveillance for hepatocellular carcinoma in patients with chronic viral hepatitis in the United States of America.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/clipboard"J Gastroenterol Hepatol. 2001;16:553-9. 
Kim DY, Kim JW, Kuromatsu R, Ahn SH, Torumura T, Sherman M. Controversies in Surveillance and Early Diagnosis of Hepatocellular Carcinoma. Oncology, 2011;81 (suppl 1):56-60.
Martin DR, Semelka RC. Health effects of ionizing radiation from diagnostic CT. Lancet. 2006;367:1712-4. 
Tsalafoutas IA, Thalassinou S, Efstathopoulos EP. A Comprehensive method for calculating patient effective dose and other dosimetric quantities from CTDICOM images. AJR Am J Roentgenol, 2012;199:133-41.
Brenner D, Elliston C, Hall E, Berdon W. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR Am J Roentgenol, 2001;176:289-96. 



Table 1 Baseline and Ranges of Radiation Dose Used in Analysis

Modality				      Values (mSv)
Baseline	Range

Abdominal ultrasound		0		0

Computerized tomography

	Chest 				7		11, 14

	Abdominal, dual phase	10		15, 20

	Abdominal, triple phase	15		22.5, 30
Table 2.  Liver Cancer Screening in Obese and Nonobese Cirrhotic Patients on the Transplant List*

Institution	Responder		Strategy� 		Percentage of CT
				Obese		Nonobese	that are triple phase
1		A		US/CT		US		20
		B		US/CT		US/CT		20
		C		US/CT		US		60

2		A		US/CT		US/CT		80
		B		US/CT		US		60
		C		US/CT		US/CT		80

3		A		CT		CT		80

4		A		CT		US		80
		B		US/CT		US/CT		80
		C		MRI		US/CT		80





*Abbreviations: US � ultrasound. CT � Computerized Tomography

�Screening with abdominal imaging was every 6 months. 



















Table 3. Liver Cancer Surveillance each year after diagnosis and treatment of liver cancer

Institution	Responder			Computerized Tomography
Chest 		Abdominal (Dual Phase)	Abdominal (Triple Phase)

1		A		2			0			4		
		B		1			0			1		
		C		1			0			3		

2		A		4			0			4		
		B		2			0			4		
C	 	0			0			2	
	
3		A		2			4			4		

4*		A		1			0			2		
		B		0			0			1		


*  Incomplete data for Responder 4 C. 



Table 4. Surveillance for Liver Cancer Recurrence in Liver Transplant Recipients*

Institution	Study (CT)				Year after Liver Transplant
		1	2	3	4	5
1		Chest				2	2	2	1	1
		Abdominal
			Dual			2	2	2	1	1

2		Chest				No standardized protocol at this institution
		Abdominal			No standardized protocol at this institution

3		Chest				2	2	1	1	1
		Abdominal	
			Triple			3	2	2	3	2

4		Chest
				Milan		2	1	0	0	0
				Beyond Milan	2	1	0	0	0
		Abdominal	
			Triple			
				Milan		2	1	1	1	1
				Beyond Milan	3	2	2	2	2

* Abbreviations: CT � computerized tomography










Radiation exposure
Page  PAGE   \* MERGEFORMAT 16













z������������F	�	�	�	�	�	�	A
G
`
f
�
�
�
�
	,-.9BDOdefg��%&.
2
4
`
�
����������������������������»Ʒ·�ƻƻƯ�駟������h�hsXKhsXKh�d�hsXK5�h�d�h�d�5�hmzB*phhmzCJaJh�ih�{_hsXKh�d�hsXKh�F�hsXKhsXKB*	ph3h�{_hsXKB*	ph3	hmzH*hmzhmzCJ0\�aJ0hsXKCJ0\�aJ04#$NOz{|��D	E	F	�
�
�

-.efg�������������������������$a$
$dha$gdsXK$a$gdsXKd�$dha$$a$������&D\|���.
a
�
�
�
�
��3;2���������������������������dhgd��dhgdsXK$a$�
�
�
�
�
V��3;02=wz ��GH4��uxz|���{}IQwADO"Q"j#l#o#�#$$f$�$�'�'�'�����������������������������ɿ�������������ɩ�������ɤ��ɰɰ�hmz6�]�	hmz6�hmz5�\�hmz5�>*\�hmzH*\�	hmz\�	hmzH*hmz	hmz5�h��hmzh�h��h�h��	h��6�	h��5�	hsXK5�hsXKhsXK5�>2=�4IQw�!n#o#�#�%�'�'�'`+a+i+�+�-j/�1�1���������������������������dh`����dh`��$dhdhdhgd���'))a+i+�+�1�1
33l7�78898�8�8:::6>;>�>�>�?�?B�B�B�C�C�D�DhEjEDFFF�F�FZG�M�MaN,P.P:P;P�P�P�P�P�P�P�P%Q&Q'Q-Q.Q0Q���������������������������������ʿڱ���ڿڔ�����j;h��hmzUh��hmz0J0>*B*ph��jh��hmzUjh��hmzUh��hmz5�h��hmz\�h��hmzhmzH*\�	hmz\�	hmz6�	hmz5�	hmzH*hmz:�1�135l7m7�7:::Z<M?BZGIL�M�M.P/P:P�TwU��������������������Q
&Fdh-DM�
����
&Fdh-DM�
����$dh��dh`����dh`��dh0Q1Q�Q�Q�Q�Q�Q�Q�QRRR'R(R*R+R�R�R�R�R�R�R�RSSSSS S!S�S�S�S�S�STT`TaTbTuTvT�T�T�T�T��������������������������������������sh��hmzCJ\�aJh��hmzCJaJ�jih��hmzU�jBh��hmzU�j	h��hmzU�j�h��hmzU�j�h��hmzUh��hmz0J0>*B*ph��jjh��hmzUh��hmzjh��hmzU-�T�T�T�T�TUUVUXUdUfUjUwUU�U�U�U�U�U�U�UHVIVKVYVmV(W1W�W�W�W�W�W�W�X�X�X�X�XGYHYIYVYgY�Y�Y
ZZZ������ŷūūū������ŷ����ū������ŷ����y��j�h��hmzU�j�
h��hmzUh��hmz6��j
h��hmzUh��hmzCJ\�aJh��hmz0J26�CJaJh��hmzCJaJh��hmz0J0>*B*ph��jP	h��hmzUh��hmzjh��hmzU/wUmVDW�WgY�Zv\]�]�^)_�_{`va�b0c�c�dAf�h.i�icj�j�����������������������
&FdhQ
&Fdh-DM�
����
&FdhP
&Fdh-DM�
����ZlZmZnZ�Z�Z�Z[[[
[[[[[�[�[�[�[�[�[�[�[�[\\\ \X\Y\Z\a\b\c\g\v\\�\�\�\�\�\�\�\�\�������������ߺ�����߬�����ߞ���ߕ߉~��p���~�j�h��hmzUh��hmzCJaJh��hmzCJ\�aJh��hmz0J9�jh��hmzU�j�h��hmzU�j�
h��hmzU�jth��hmzUh��hmz0J2h��hmzjh��hmzUh��hmz0J0>*B*ph�,�\]]�]�]�^�^	__a`g`{`�`�`�`!a"a#aLaMaNa]ava}a�a�abb	b�b�b�b�b�b�b�b�b�b�b�bccmcnc�c������������ߨ�������ߋ���~��߶�p���߶��j7h��hmzUh��hmz0J2CJaJ�jnh��hmzUh��hmz0J0>*B*ph��j�h��hmzUjh��hmzUh��hmzCJ\�aJh��hmz6�]�h��hmz6�h��hmzh��hmzCJaJh��hmz0J26�CJaJ,�c�c�c�c�c�c d�d�d�deee#e$e&e'e�e�e�e�e�e�e�efff1f2fAfBf�f�f�f�f�f�f�f$g%g&g.g/g1g2g�g�����ǽ��Я�����С�����Г�����Ѕ������w�������j�h��hmzU�j�h��hmzU�j�h��hmzU�j�h��hmzU�jmh��hmzUh��hmzPJ\�h��hmzPJh��hmzh��hmz0J0>*B*ph�jh��hmzU�j�h��hmzU-�g�g�g�g�ghhThUhVhnhohii~i�i=jPjcj�j�j�j�j�j;k�k`l�l�l�l�lnntn�n�no�o�o�o�o�o5p?p�q�����������иаиШ��Й������z����z���r���z�hmzCJaJhmz>*CJaJhmzCJaJhmz5�CJaJ	hmz5�hmzh��hmz6�\�]�h��hmz\�h��hmz6�h��hmz6�]��j7h��hmzUh��hmzh��hmz0J0>*B*ph�jh��hmzU�jh��hmzU,�j�j�j�j:k;kZkikjk�k�k�k�k�k�k�k�k�k`lal�l�l�l�l�l�lm��������������������������dh	���^�`��$��dh^��m'm=m>mOmPmamwm�m�m�m�m�m�m�m�mnnn	n
nnn
nnnnnn����������������������������dhnnnnnnnntnun�n�n�n�nooo%o6oEoGoYoZomo~oo�����������������������������dh^��`���O��dh^�O`��dh$dho�o�o�o�o�o�o�o3p?pUpapupvp�p�p�pqq$q%q.qCq^qkqxq�q���������������������������O��dh^�O`��$dhdh�q�q�q�q�q�q�q�q�q�q�q�q�q�q�qrrrrrr r!r"r#r$r%r&r'r����������������������������$a$gd�idh�q�q�q�q�q�q�q�q�q�q�q�q�q�qrrrrr%r&r'r��������������˼��� jh�ih�iCJUaJ�*h�>�CJaJmHnHu�*jh�ih�iCJUaJh�ihmzCJaJh�ih�iCJaJhmyjhmyUhmz20p�1����/ ��=!��"��#��$��%�������20p�1����/ ��=!��"��#��$��%�������;D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Capocaccia%20R%5BAuthor%5D&cauthor=true&cauthor_uid=17555459/D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Sant%20M%5BAuthor%5D&cauthor=true&cauthor_uid=175554595D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Berrino%20F%5BAuthor%5D&cauthor=true&cauthor_uid=175554599D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Simonetti%20A%5BAuthor%5D&cauthor=true&cauthor_uid=175554591D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Santi%20V%5BAuthor%5D&cauthor=true&cauthor_uid=175554599D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Trevisani%20F%5BAuthor%5D&cauthor=true&cauthor_uid=17555459'D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=EUROCARE%20Working%20Group%5BCorporate%20Author%5D�D���y������K����y������K�vhttp://www.ncbi.nlm.nih.gov/pubmed/?term=sant+m%2C+santi+v�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/19224838�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/14623619�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/12827551�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/177678985D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Llovet%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=146677509D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Burroughs%20A%5BAuthor%5D&cauthor=true&cauthor_uid=146677501D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Bruix%20J%5BAuthor%5D&cauthor=true&cauthor_uid=14667750�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/14667750�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/20203642�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/23237697�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/23943387�D���y������K����y������K�*http://www.srtr.org/�D���y������K����y������K�*http://Www.unos.org/9D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=El-Serag%20HB%5BAuthor%5D&cauthor=true&cauthor_uid=213179905D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Davila%20JA%5BAuthor%5D&cauthor=true&cauthor_uid=21317990�D���y������K����y������K�Xhttp://www.ncbi.nlm.nih.gov/pubmed/213179901D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Tong%20MJ%5BAuthor%5D&cauthor=true&cauthor_uid=113505533D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Blatt%20LM%5BAuthor%5D&cauthor=true&cauthor_uid=11350553/D���y������K����y������K��http://www.ncbi.nlm.nih.gov/pubmed?term=Kao%20VW%5BAuthor%5D&cauthor=true&cauthor_uid=11350553�D���y������K����y������K�Zhttp://www.ncbi.nlm.nih.gov/pubmed/clipboard^V���������666666666vvvvvvvvv6666668666666666666666666666666666�6666666666�666666666666hH66666666666666666666666666666666666666666666666666666666666666666�62���� 0@P`p������2(�� 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p��8X�V~_HmH	nH	sH	tH	L`�LNormal*$ CJKHPJ_HaJmH	sH	tH@@	Heading 1@&
&F
&Fhh	Heading 2@&
&F
&F�(�$B*
ph6_�OJQJCJ^JaJDA �DDefault Paragraph FontVi�V
0Table Normal :V�4�4�
la�(k �(
0No List6�/��6	WW8Num2z1OJQJ^J2�/�2	WW8Num2z2OJQJ2�/�2	WW8Num2z3OJQJJ�/�!JAbsatz-StandardschriftartDA �1DDefault Paragraph FontJ�/�AJWW-Default Paragraph FontP�/�QPWW-Absatz-StandardschriftartR�/�aRWW-Absatz-Standardschriftart1F�/�qFDefault Paragraph Font12�/�2	WW8Num2z0OJQJ2�/�2	WW8Num3z0OJQJ6�/�6	WW8Num3z1OJQJ^J2�/�2	WW8Num3z2OJQJ2�/�2	WW8Num4z0OJQJ6�/��6	WW8Num4z1OJQJ^J2�/��2	WW8Num4z2OJQJ2�/��2	WW8Num5z0OJQJ6�/�6	WW8Num5z1OJQJ^J2�/�2	WW8Num5z2OJQJ2�/�!2	WW8Num6z0OJQJ6�/�16	WW8Num6z1OJQJ^J2�/�A2	WW8Num6z2OJQJ2�/�Q2	WW8Num7z0OJQJ6�/�a6	WW8Num7z1OJQJ^J2�/�q2	WW8Num7z2OJQJT�/�TWW-Absatz-Standardschriftart11V�/�VWW-Absatz-Standardschriftart1116�/�6	WW8Num1z0OJQJ^J6�/�6	WW8Num1z1OJQJ^JX�/�X WW-Absatz-Standardschriftart1111Z�/��Z!WW-Absatz-Standardschriftart11111\�/��\"WW-Absatz-Standardschriftart1111116�/��6BulletsOJPJQJ^JFU`�F	Hyperlink>*B*_H�mH�ph�sH�tH�B�/�Bapple-converted-space �o�! jrnlF�/�1FHeading 1 Char5CJ0KH\aJ0V�/�AVHeading 2 Char!B*
CJKHOJQJ^JaJph6_�V�/�QVBalloon Text CharCJKHOJ	PJQJ	^J	aJ>�/�a>Header CharCJKHPJaJ>�/�q>Footer CharCJKHPJaJ2�/�2ListLabel 1^J*�o�*	highlight2�/�2ListLabel 2^J2�/�2ListLabel 3^J(�/�(citation2�/��2ListLabel 4^J2�/��2ListLabel 5^J2�/��2ListLabel 6^JN�NHeading
@���x$OJQJCJPJ
^J	aJ6B6	Body Text
A��x(/"(ListB^J	H"2HCaption
C�x�x$CJ6^J	aJ].�B.IndexD$^J	@�R@caption
E�x�x$
6^J	]B�bBCaption1
F�x�x$
6^J	]D�rDList ParagraphG^��]�`�(��(Title1H$��$descI*��*detailsJH��HBalloon TextKOJ	QJ	CJ^J	aJ6�6HeaderL
�H�$$6 �6FooterM
�H�$$<��<Table ContentsN$d�/��d
Table HeadingO$$*$1$a$5�KHPJ\�_HmH	sH	tH4�O4title1PCJPJaJ2�O2desc2QCJPJaJ8�"8details1RCJPJaJ4�24articletype7SH�BHauthors4TdhB*phfffCJPJaJZ�RZ
citationline5Udh���B*phfffCJPJaJPK!����[Content_Types].xml���j�0E����ж�r�(��΢Iw},��-j��4	��w�P�-t#bΙ{U�����T�U^h�d}㨫��)��*1P�'��	�^��W��0)��T�9<�l�#��$yi}��;�~@��(��H����u�*Dנz��/0�ǰ��$��X��3aZ����,�D0j~�3߶�b��~i>���3�\`�?�/�[���G��\�!�-�Rk.�s�Ի�..���a濭?��PK!�֧�6_rels/.rels���j�0���}Q��%v/��C/�}�(h"���O�
����=������ ����C?�h�v=��Ʌ��%[xp��{۵_�Pѣ<�1�H�0���O�R�Bd���JE�4b$��q_����6L�R�7`������0̞O��,�En7�Li�b��/�S���e��е�����PK!ky���theme/theme/themeManager.xml�M
� @�}�w��7c�(Eb�ˮ��C�AǠҟ����7��՛K
Y,�
�e�.���|,���H�,l����xɴ��I�sQ}#Ր���� ֵ+�!�,�^�$j=�GW��)�E�+&
8���PK!����Ptheme/theme/theme1.xml�YOo�6��w toc'vu�ر�-M�n�i���P�@�I}��úa��m�a[�إ�4�:lЯ�GR��X^�6؊�>$�������!)O�^�r�C$�y@�����/�yH*��񄴽)�޵��߻��UDb�`}"�qۋ�Jח���X^�)I`n�E���p)���li�V[]�1M<������O�P��6r�=���z�gb�Ig��u��S�eb��O������R�D۫����qu	�g��Z����o~ٺlAp�lx�pT0���+[}`j���zA��V�2�F���i�@�q�v�֬5\|��ʜ̭N��le�X�ds���jcs���7���f����
��W��+�Ն�7����`���g�Ș��J���j|��h(�K��D-����
dX��iJ�؇(��x$(��:��;�˹!�I_�T��S1�����?E��?�����?ZBΪm���U/������?�~����xY���'���y5�g&΋/����ɋ�>���G�M�Ge���D�����3Vq%'#q�����$�8��K�����)f�w9:ĵ��
x}r�x����w���r�:\TZaG�*�y8I�j�bR��c|XŻ�ǿ�I
u3KG�nD1�NIB�s���
��R��u���K>V�.EL+M2�#'�f��i~�V��vl�{u8��z��H�
�*���:�(W�☕
~��J�T�e\O*�tHG��HY��}KN�P�*ݾ˦���TѼ�9/#��A7�qZ��$*c?���qU��n��w�N��%��O��i�4=3ڗP��
����1�P�m\\9���������Mؓ�2a�D�]�;Yt�\��[x����]�}Wr��|�]��g-���
eW�
�)6-r��CS�j��
i�d	�DЇA�ΜIqbJ#x�꺃6k���#��A�Sh��&ʌt(Q�%��p%m��&]�caSl=�X�����\P�1�Mh�9�M��V�dDA��aV�B��[݈fJ�íP|8�քA�V^��f
�H��n���-��"�d>�z��n��NJ�	�ة�>�b���&����2��v����Kyϼ��D:����,AGm��\nz��i�Ù��.uχYC�6�OMf��3o�r��$��5�����NH�T[XF64�T,ќ���M0�E)`#�5�XY�`�פ;��%�1�U�٥m;���R>QD����D�cp�U�'��&LE�/p���m���%]�����8fi��r�S4�d7y\�`�J�n���ί�I�R��3U�~7+���׸#��m�q�BiD���������i*�L6�9�m�Y&���i���HE��=(K&�N!V�.K�e�LD�ĕ�{D	����vEꦚde��NƟ��e�(�MN9ߜR�6����&3(��a���/D��U�z�<�{ˊ�Y��ȳ����V���)�9�Z[��4^n��5���!J��?��Q�3�eBo�C����M����m<�.�vp�����IY�f���Z�Y_p�[�=al-�Y�}Nc͙���ŋ4vfa��vl����'S��A�8�|�*u�{��-�ߟ0%M0�7%����<���ҍ���PK!
ѐ��'theme/theme/_rels/themeManager.xml.rels��M
�0���wooӺ�&݈Э���5
6?$Q��
�,.�a��i����c2�1h�:�q��m��@RN��;d�`��o7�g�K(M&$R(.1�r'J��ЊT���8��V�"��AȻ�H�u}��|�$�b{��P����8�g/]�QAsم(����#��L�[������PK-!����[Content_Types].xmlPK-!�֧�6+_rels/.relsPK-!ky���theme/theme/themeManager.xmlPK-!����P�theme/theme/theme1.xmlPK-!
ѐ��'�	theme/theme/_rels/themeManager.xml.relsPK]�
<?xml version="1.0" encoding="UTF-8" standalone="yes"?>
<a:clrMap xmlns:a="http://schemas.openxmlformats.org/drawingml/2006/main" bg1="lt1" tx1="dk1" bg2="lt2" tx2="dk2" accent1="accent1" accent2="accent2" accent3="accent3" accent4="accent4" accent5="accent5" accent6="accent6" hlink="hlink" folHlink="folHlink"/>'j�����4�����	BDFHJLO�
�'0Q�TZ�\�c�g�q'r:=?ABDEFGM�2�1wU�jmno�q'r;<>@CHIJKL:H�H�H�H&I-I0I�I�I�IJ'J*J�J�J�JKK K�K�KLaLuL�L�LUM�M�MHN�P�PGQ�QRlR�RS
SS�S�S�S�STTYTaT�T�T�T�X"YLY�YZ�Z�Z�Z[m[�[�[�\]#]&]�]�]�]^1^A^�^�^�^%_._1_�_�_`U`n`'jX��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��$<?O!����8�@�����������0�(	�
��B
�S����	?���_GoBack
articleTopaF�c(jaF�c(jao����+9����


�
�
�
-0#1*
:
������ � � � ,!/!�!�!�!�!i#v#E$H$%
%�%�%4&7&T&W&v&y&�&�&D'G'U'X'�'�'~(�(�(�(�)�)�)�)�)�)�)�)�+�+�+,t-w-�-�-�-�-�-�-<.?.�.�.)/,/�/�/1111|11�1�1�2�2d5p5�6�677d7i7�9�9q<x<#=&=\=_=FBQB3F@F�K�K�L�L�L�L�L�LZM^M_MdMzMM�M�MmNrN�N�N�N�N*O1ODOIO�O�O
PP,P2P6P<PRPZP_PePqPyP�P�POQVQ�Q�QuR|RTT�TUU#UqU|U�U�U�U�U�U�UVVVV�V�V�V�V�V�VWW�W�W�X�X�X�X�X�X�X�XgYlYvY{Y�Y�Y�Y�Y�Y�Y�Z�Z�[�[�[�[�[�[�[�[�[�[\	\
\\Q\_\�\�\�]�]�_�_�`�`�`�`�`�`�`�`a#a9a@a�a�a�a�a�a�abbFbPb�b�b�b�bUcXc,d4d�d�d�i�i�i�i�i�i�i�i�i�i�ij%j(j�i�i�ij(j||Ee?G:H�H�H.I0I�I�I(J*J�J�JK K�KLvL�LVM�MIN�PHQ�QmR�RSS�S�STTbT�T�T�XMY�Y�Z�Z[m[�[�\$]&]�]�]2^A^�^�^/_1_�_`o`�i�i�i�ij(j����������������������P���^��`�P���@����@^�@`�������0���^��`�0���`����`^�``����������^��`����������^��`��������^�`������`���^��`�`���0���0^�0`���������^��`���.�8����8^�8`���OJQJ^Jo�������^��`���OJQJ�������^�`���OJQJ���p����p^�p`���OJQJ^Jo��	�����	^��	`���OJQJ���@����@^�@`���OJQJ���������^��`���OJQJ^Jo�����^�`���OJQJ������������WW8Num2���M��mymz�s<�.?sXK�e�i�i���
/��"�|����>��d��i�i�@�@
'j`@��Unknown������������G��* ��Times New Roman5��Symbol3.��* ��ArialO.��
�k9?Lucida Sans Unicode7���K@�CambriaW�font292Times New Roman?=�	�* �Courier New;��Wingdings_�OpenSymbolArial Unicode MS5.�*a��TahomaG5��
	�����h�MS Mincho-�3� fgA���� B�Cambria Math#� �h��#���#��G�
Z6����
Z6�� 0�i�i3� ��X�����������������s<�!xx���Vignan ManneSSaab����Oh��+'��0p�������	�
 ,8
DPX`h�Vignan ManneNormalSSaab2Microsoft Office Word@@TI?���@�ai�J�@�ai�J��
Z����՜.��+,��D��՜.��+,��4�hp��������
���Microsoft�6�iTitle� 8@_PID_HLINKS�Al�]Q-http://www.ncbi.nlm.nih.gov/pubmed/clipboard�?^N_http://www.ncbi.nlm.nih.gov/pubmed?term=Kao%20VW%5BAuthor%5D&cauthor=true&cauthor_uid=11350553�V=Kahttp://www.ncbi.nlm.nih.gov/pubmed?term=Blatt%20LM%5BAuthor%5D&cauthor=true&cauthor_uid=11350553�-H`http://www.ncbi.nlm.nih.gov/pubmed?term=Tong%20MJ%5BAuthor%5D&cauthor=true&cauthor_uid=11350553�/?E,http://www.ncbi.nlm.nih.gov/pubmed/21317990�iCBbhttp://www.ncbi.nlm.nih.gov/pubmed?term=Davila%20JA%5BAuthor%5D&cauthor=true&cauthor_uid=21317990�X"?dhttp://www.ncbi.nlm.nih.gov/pubmed?term=El-Serag%20HB%5BAuthor%5D&cauthor=true&cauthor_uid=21317990�EB<http://www.unos.org/�X_9http://www.srtr.org/�"06,http://www.ncbi.nlm.nih.gov/pubmed/23943387� >3,http://www.ncbi.nlm.nih.gov/pubmed/23237697� 70,http://www.ncbi.nlm.nih.gov/pubmed/20203642�#5-,http://www.ncbi.nlm.nih.gov/pubmed/14667750�Xv*`http://www.ncbi.nlm.nih.gov/pubmed?term=Bruix%20J%5BAuthor%5D&cauthor=true&cauthor_uid=14667750�Ww'dhttp://www.ncbi.nlm.nih.gov/pubmed?term=Burroughs%20A%5BAuthor%5D&cauthor=true&cauthor_uid=14667750�qN$bhttp://www.ncbi.nlm.nih.gov/pubmed?term=Llovet%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=14667750�/8!,http://www.ncbi.nlm.nih.gov/pubmed/17767898�#;,http://www.ncbi.nlm.nih.gov/pubmed/12827551�&5,http://www.ncbi.nlm.nih.gov/pubmed/14623619�%4,http://www.ncbi.nlm.nih.gov/pubmed/19224838�ru;http://www.ncbi.nlm.nih.gov/pubmed/?term=sant+m%2C+santi+v�t [http://www.ncbi.nlm.nih.gov/pubmed?term=EUROCARE%20Working%20Group%5BCorporate%20Author%5D�Hudhttp://www.ncbi.nlm.nih.gov/pubmed?term=Trevisani%20F%5BAuthor%5D&cauthor=true&cauthor_uid=17555459�\y`http://www.ncbi.nlm.nih.gov/pubmed?term=Santi%20V%5BAuthor%5D&cauthor=true&cauthor_uid=17555459�R{	dhttp://www.ncbi.nlm.nih.gov/pubmed?term=Simonetti%20A%5BAuthor%5D&cauthor=true&cauthor_uid=17555459�.bhttp://www.ncbi.nlm.nih.gov/pubmed?term=Berrino%20F%5BAuthor%5D&cauthor=true&cauthor_uid=17555459�t_http://www.ncbi.nlm.nih.gov/pubmed?term=Sant%20M%5BAuthor%5D&cauthor=true&cauthor_uid=17555459�}ehttp://www.ncbi.nlm.nih.gov/pubmed?term=Capocaccia%20R%5BAuthor%5D&cauthor=true&cauthor_uid=17555459�	

 !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMN����PQRSTUVWXYZ[\]����_`abcdefghijklmnopqrstuvwxyz{|����~���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������Root Entry��������	�F`����J���Data
������������O1Table����^�=WordDocument����h�SummaryInformation(������������}DocumentSummaryInformation8����������CompObj������������y������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������
����	�F'Microsoft Office Word 97-2003 Document
MSWordDocWord.Document.8�9�q

Youez - 2016 - github.com/yon3zu
LinuXploit