. _:b446299362 "4"^^ . . _:b446299850 . _:b446299373 "4"^^ . _:b446299372 "4"^^ . _:b446299353 . _:b446299818 . _:b446299375 "4"^^ . _:b446299374 "4"^^ . _:b446299369 "4"^^ . _:b446299368 "4"^^ . _:b446299606 . . _:b446299371 "4"^^ . _:b446299532 . _:b446299516 . _:b446299370 "4"^^ . . . _:b446299630 . _:b446299381 "4"^^ . _:b446299380 "4"^^ . . _:b446299383 "4"^^ . _:b446299679 . _:b446299357 . . _:b446299420 . _:b446299382 "4"^^ . _:b446299370 . _:b446299377 "4"^^ . _:b446299376 "4"^^ . _:b446299451 . _:b446299379 "4"^^ . . _:b446299926 . _:b446299378 "4"^^ . _:b9111678 "25,26 One reason for more neurological AEs observed in the trabedersen groups may be the mode of administration of trabedersen through CED (ie, the infusion process through an implanted catheter).>>12<< Although events related to the implantation and the procedure of drug administration cannot be completely avoided, those observed during this study were manageable, and their incidence can be further reduced by intensified training of the" . _:b9111673 "22,23 This particularly applies to immuno-based therapies, such as trabedersen, which rely on building an immune response over time.23,>>24<< Indeed, the results of this study show that the clinically relevant beneficial effect of trabedersen increases over time, which was visible especially in the 10 \u00B5M trabedersen group and was most evident at 14 months regarding tumor" . _:b446299423 . . . _:b446299389 "3"^^ . _:b446299796 . _:b446299388 "4"^^ . _:b446299460 . . . _:b446299391 "3"^^ . _:b446299545 . . _:b446299390 "3"^^ . _:b446299385 "4"^^ . _:b446299700 . . _:b446299384 "4"^^ . . _:b446299387 "4"^^ . _:b446299386 "4"^^ . _:b446299397 "3"^^ . . . _:b446299396 "3"^^ . _:b446299399 "3"^^ . _:b446299398 "3"^^ . _:b446299641 . . _:b446299393 "3"^^ . . _:b446299392 "3"^^ . _:b446299395 "3"^^ . _:b446299394 "3"^^ . _:b446299756 . _:b446299405 "3"^^ . . _:b446299404 "3"^^ . _:b446299407 "3"^^ . . _:b446299777 . _:b446299406 "3"^^ . _:b446299401 "3"^^ . . _:b446299400 "3"^^ . _:b446299403 "3"^^ . . _:b446299402 "3"^^ . _:b446299413 "3"^^ . _:b446299412 "3"^^ . _:b446299912 . _:b446299415 "3"^^ . . _:b446299414 "3"^^ . _:b446299409 "3"^^ . . _:b446299408 "3"^^ . _:b446299411 "3"^^ . . _:b446299410 "3"^^ . . . . . _:b446299421 "3"^^ . . . _:b9111676 . _:b446299420 "3"^^ . . _:b446299423 "3"^^ . _:b446299564 . _:b446299422 "3"^^ . _:b446299579 . . _:b446299417 "3"^^ . _:b446299449 . _:b446299416 "3"^^ . _:b446299480 . _:b446299419 "3"^^ . _:b446299418 "3"^^ . . _:b446299429 "3"^^ . _:b446299428 "3"^^ . . _:b9111682 . _:b446299431 "3"^^ . _:b9111673 . _:b446299430 "3"^^ . _:b446299865 . . _:b446299425 "3"^^ . _:b9111665 . _:b446299424 "3"^^ . _:b446299356 . _:b446299329 . _:b446299427 "3"^^ . _:b446299426 "3"^^ . . _:b446299437 "3"^^ . . . _:b446299512 . . _:b446299436 "3"^^ . _:b446299439 "3"^^ . _:b446299859 . . _:b446299438 "3"^^ . . _:b446299433 "3"^^ . . . . . _:b446299432 "3"^^ . . _:b446299435 "3"^^ . . . _:b446299434 "3"^^ . _:b446299546 . _:b446299445 "3"^^ . . . _:b446299444 "3"^^ . _:b446299681 . _:b446299447 "3"^^ . . _:b446299909 . _:b446299474 . _:b446299446 "3"^^ . _:b446299378 . _:b446299574 . _:b446299908 . _:b446299441 "3"^^ . . _:b446299911 . _:b446299884 . _:b446299440 "3"^^ . _:b446299910 . _:b446299443 "3"^^ . . _:b446299905 . . . _:b446299442 "3"^^ . . _:b446299904 . _:b446299453 "3"^^ . _:b9111683 "Pseudoprogression, a transient initial increase of the enhancing lesion,>>32<< was seen in about 10% of trabedersen-treated patients in this study." . _:b446299907 . _:b446299452 "3"^^ . . _:b446299906 . _:b446299455 "3"^^ . _:b446299917 . _:b446299454 "3"^^ . _:b446299916 . _:b446299904 . _:b446299449 "3"^^ . _:b446299919 . _:b446299285 . _:b446299448 "3"^^ . _:b446299918 . _:b446299451 "3"^^ . _:b9111669 . _:b446299913 . _:b446299450 "3"^^ . _:b446299497 . _:b446299912 . _:b446299364 . _:b446299461 "3"^^ . _:b9111664 "13,14 In contrast to other CED studies,>>15<<,16 a single catheter was placed into the solid and contrast-enhancing area of the largest tumor lesion." . _:b446299915 . _:b446299460 "3"^^ . _:b9111670 . . . _:b446299914 . . _:b446299463 "3"^^ . . _:b446299925 . _:b446299462 "3"^^ . _:b446299924 . _:b446299457 "3"^^ . _:b446299927 . _:b446299365 . . . _:b446299456 "3"^^ . _:b446299926 . _:b446299459 "3"^^ . _:b446299921 . _:b446299458 "3"^^ . _:b446299920 . _:b446299469 "3"^^ . _:b446299923 . _:b446299468 "3"^^ . _:b446299508 . _:b446299922 . . _:b446299471 "3"^^ . _:b446299955 . . _:b446299933 . _:b446299720 . . _:b446299470 "3"^^ . _:b446299932 . _:b446299986 . . _:b446299465 "3"^^ . _:b446299935 . _:b446299464 "3"^^ . _:b446299934 . . _:b446299467 "3"^^ . _:b446299528 . _:b446299929 . _:b446299466 "3"^^ . _:b446299928 . _:b446299676 . _:b446299477 "3"^^ . _:b446299838 . _:b446299931 . _:b446299476 "3"^^ . _:b446299390 . _:b446299930 . . _:b446299479 "3"^^ . _:b446299941 . _:b446299429 . _:b446299478 "3"^^ . _:b446299607 . _:b446299940 . _:b446299858 . . _:b446299473 "3"^^ . _:b446299448 . _:b446299848 . _:b446299943 . _:b446299748 . _:b446299472 "3"^^ . _:b446299942 . . _:b446299828 . _:b446299475 "3"^^ . _:b446299321 . _:b446299937 . _:b446299474 "3"^^ . _:b446299936 . _:b446299485 "3"^^ . _:b446299810 . _:b446299939 . _:b446299383 . _:b446299484 "3"^^ . _:b446299713 . _:b446299938 . _:b446299487 "3"^^ . _:b446299303 . _:b446299949 . _:b446299486 "3"^^ . . _:b446299948 . . . _:b446299481 "3"^^ . _:b446299951 . _:b446299480 "3"^^ . _:b446299639 . _:b446299950 . _:b446299483 "3"^^ . _:b446299945 . . _:b446299482 "3"^^ . _:b446299567 . _:b446299944 . . _:b446299493 "3"^^ . _:b446299947 . _:b446299492 "3"^^ . _:b446299946 . _:b446299495 "3"^^ . . _:b446299957 . _:b446299478 . _:b446299494 "3"^^ . . _:b446299956 . _:b446299489 "3"^^ . _:b446299684 . _:b446299959 . _:b446299488 "3"^^ . _:b446299908 . _:b446299893 . _:b446299958 . _:b446299491 "3"^^ . _:b446299953 . _:b446299490 "3"^^ . _:b446299952 . _:b446299501 "3"^^ . _:b446299955 . . _:b446299500 "3"^^ . . _:b446299954 . . . _:b446299503 "3"^^ . . _:b446299965 . _:b446299502 "3"^^ . _:b446299964 . _:b446299497 "3"^^ . _:b446299531 . . _:b446299967 . _:b446299496 "3"^^ . _:b446299966 . _:b446299499 "3"^^ . _:b446299961 . . _:b446299498 "3"^^ . . _:b446299960 . _:b446299509 "2"^^ . _:b446299933 . _:b446299963 . . _:b446299855 . _:b446299508 "3"^^ . _:b446299962 . _:b446299511 "2"^^ . _:b446299973 . _:b446299510 "2"^^ . _:b446299499 . . _:b446299972 . _:b446299505 "3"^^ . . . _:b446299975 . . _:b446299504 "3"^^ . . _:b446299974 . . _:b446299507 "3"^^ . _:b446299969 . . _:b446299506 "3"^^ . . _:b446299833 . _:b446299968 . _:b446299517 "2"^^ . _:b446299971 . _:b446299516 "2"^^ . _:b446299970 . _:b446299519 "2"^^ . _:b446299981 . . _:b446299951 . _:b446299518 "2"^^ . . _:b446299980 . _:b446299463 . _:b446299513 "2"^^ . . _:b446299983 . _:b446299512 "2"^^ . _:b446299982 . _:b446299515 "2"^^ . _:b446299977 . _:b446299514 "2"^^ . . _:b446299976 . _:b446299525 "2"^^ . . _:b446299786 . . _:b446299979 . _:b446299524 "2"^^ . _:b446299350 . _:b446299978 . _:b446299527 "2"^^ . _:b446299406 . _:b446299942 . _:b446299645 . _:b446299526 "2"^^ . _:b446299527 . _:b446299521 "2"^^ . . . _:b446299520 "2"^^ . . _:b9111678 . _:b446299523 "2"^^ . _:b446299522 . _:b446299985 . _:b446299522 "2"^^ . _:b446299308 . _:b446299984 . _:b446299533 "2"^^ . _:b446299374 . . _:b9111671 . . _:b9111675 . _:b446299987 . _:b446299532 "2"^^ . _:b446299986 . _:b9111674 . _:b446299535 "2"^^ . . . _:b446299873 . _:b446299534 "2"^^ . _:b446299750 . _:b446299587 . _:b446299529 "2"^^ . . _:b446299300 . . _:b446299528 "2"^^ . _:b446299531 "2"^^ . _:b446299530 "2"^^ . _:b9111672 . _:b446299430 . _:b446299541 "2"^^ . _:b446299540 "2"^^ . . . _:b446299543 "2"^^ . . _:b446299542 "2"^^ . _:b446299537 "2"^^ . _:b446299856 . _:b446299536 "2"^^ . _:b446299539 "2"^^ . . _:b446299538 "2"^^ . _:b446299467 . _:b446299751 . _:b446299549 "2"^^ . . _:b446299379 . _:b446299548 "2"^^ . _:b446299801 . . _:b446299551 "2"^^ . _:b446299550 "2"^^ . _:b446299578 . _:b446299545 "2"^^ . . _:b446299544 "2"^^ . _:b446299547 "2"^^ . _:b446299366 . _:b446299546 "2"^^ . _:b446299557 "2"^^ . . _:b446299556 "2"^^ . _:b446299559 "2"^^ . _:b446299670 . _:b446299558 "2"^^ . . _:b446299553 "2"^^ . _:b446299552 "2"^^ . _:b446299604 . . _:b446299555 "2"^^ . _:b446299554 "2"^^ . . _:b446299565 "2"^^ . _:b446299564 "2"^^ . _:b9111681 . . _:b446299567 "2"^^ . . _:b446299566 "2"^^ . _:b446299637 . _:b9111657 . . . _:b446299561 "2"^^ . _:b446299753 . _:b446299560 "2"^^ . _:b9111659 . _:b446299563 "2"^^ . _:b446299827 . . _:b446299840 . _:b446299562 "2"^^ . . . _:b446299789 . _:b446299573 "2"^^ . . _:b446299572 "2"^^ . _:b446299727 . _:b446299575 "2"^^ . _:b9111677 "were taken from patients of the control group. Generally, the frequency and nature of the reported events were typical for patients with primary brain tumors who usually have a large number of accompanying neurological disorders.25,>>26<< One reason for more neurological AEs observed in the trabedersen groups may be the mode of administration of trabedersen through CED (ie, the infusion process through an implanted catheter)." . _:b446299689 . _:b446299574 "2"^^ . _:b446299569 "2"^^ . _:b9111664 . _:b446299452 . _:b446299568 "2"^^ . _:b446299439 . . _:b446299506 . _:b446299571 "2"^^ . _:b446299570 "2"^^ . . _:b446299581 "2"^^ . _:b446299580 "2"^^ . _:b446299711 . _:b446299631 . _:b446299583 "2"^^ . _:b446299780 . _:b446299582 "2"^^ . _:b446299577 "2"^^ . . _:b446299576 "2"^^ . . _:b446299579 "2"^^ . _:b446299578 "2"^^ . _:b446299548 . . _:b446299589 "2"^^ . _:b446299384 . . _:b446299542 . . _:b446299588 "2"^^ . _:b446299726 . _:b446299591 "2"^^ . _:b446299590 "2"^^ . _:b446299457 . . _:b446299585 "2"^^ . _:b446299409 . _:b446299584 "2"^^ . _:b446299587 "2"^^ . _:b446299775 . _:b446299586 "2"^^ . _:b446299597 "2"^^ . _:b446299596 "2"^^ . _:b9111679 . _:b446299599 "2"^^ . _:b446299444 . . _:b446299598 "2"^^ . . . _:b446299593 "2"^^ . _:b446299475 . . . _:b446299592 "2"^^ . . _:b446299595 "2"^^ . . _:b446299373 . _:b446299594 "2"^^ . _:b446299605 "2"^^ . _:b446299737 . _:b446299826 . _:b446299604 "2"^^ . _:b446299534 . _:b446299761 . _:b446299607 "2"^^ . _:b446299606 "2"^^ . _:b446299601 "2"^^ . . _:b446299600 "2"^^ . _:b446299603 "2"^^ . . _:b446299602 "2"^^ . . _:b446299613 "2"^^ . _:b446299702 . _:b446299612 "2"^^ . . _:b446299615 "2"^^ . _:b446299614 "2"^^ . . _:b446299609 "2"^^ . _:b446299608 "2"^^ . _:b446299788 . _:b446299611 "2"^^ . . _:b446299610 "2"^^ . _:b446299493 . . _:b446299621 "2"^^ . . _:b446299620 "2"^^ . _:b446299623 "2"^^ . _:b446299361 . _:b446299622 "2"^^ . _:b446299617 "2"^^ . _:b446299616 "2"^^ . _:b446299619 "2"^^ . _:b446299618 "2"^^ . . _:b446299629 "2"^^ . . _:b446299874 . . _:b446299628 "2"^^ . _:b446299725 . _:b446299733 . _:b446299631 "2"^^ . _:b446299651 . _:b446299630 "2"^^ . . _:b446299764 . _:b446299625 "2"^^ . _:b446299413 . _:b446299624 "2"^^ . _:b446299898 . _:b446299343 . . _:b446299412 . _:b446299627 "2"^^ . _:b446299495 . _:b446299543 . . _:b446299626 "2"^^ . _:b446299637 "2"^^ . . _:b446299636 "2"^^ . . _:b446299639 "2"^^ . . _:b446299638 "2"^^ . . _:b446299633 "2"^^ . _:b446299566 . _:b446299338 . _:b446299632 "2"^^ . _:b446299635 "2"^^ . . . . . _:b446299634 "2"^^ . . . _:b446299645 "2"^^ . . _:b446299644 "2"^^ . . _:b446299647 "2"^^ . _:b446299646 "2"^^ . _:b446299641 "2"^^ . . _:b446299640 "2"^^ . . . _:b446299643 "2"^^ . _:b446299642 "2"^^ . _:b446299830 . . _:b446299783 . . _:b446299974 . _:b446299450 . _:b446299526 . . _:b9111680 . . . . . . . _:b446299519 . _:b446299820 . _:b446299381 . _:b446299653 . _:b446299752 . _:b446299481 . _:b446299925 . _:b446299678 . . . _:b446299602 . _:b446299296 . _:b446299585 . . _:b446299800 . . . _:b446299924 . . _:b446299556 . . . . . . . . . _:b446299935 . _:b446299304 . _:b446299500 . . _:b446299305 . _:b446299915 . . . _:b446299707 . _:b446299959 . _:b446299875 . _:b446299976 . _:b446299719 . . _:b446299349 . _:b446299491 . . . _:b446299831 . _:b446299706 . _:b446299541 . _:b446299966 . . . _:b446299401 . . _:b446299399 . "PMC0" . . . _:b446299653 . _:b446299652 . _:b446299655 . _:b446299654 . _:b446299649 . . _:b446299648 . _:b446299432 . . _:b446299426 . _:b446299651 . _:b9111675 "Despite the clinical relevance of the treatment effects observed with trabedersen and the consistency with findings from previous phase I/II studies,>>12<< the hypotheses generated in this phase II study need to be confirmed in prospective clinical studies." . _:b446299385 . . _:b446299650 . _:b446299344 . _:b446299923 . _:b446299661 . . _:b446299660 . _:b446299663 . . _:b446299662 . . _:b446299657 . . . _:b446299656 . . . _:b446299659 . _:b446299518 . . . _:b446299658 . _:b446299660 . _:b446299669 . _:b446299668 . _:b446299671 . _:b446299670 . _:b446299728 . _:b446299665 . _:b446299576 . _:b446299664 . _:b446299382 . . . _:b446299766 . _:b446299667 . _:b446299666 . . _:b446299677 . . _:b446299881 . . _:b446299676 . _:b446299419 . _:b446299625 . _:b446299679 . . _:b446299678 . _:b446299673 . _:b446299672 . . _:b446299672 . _:b446299380 . _:b446299677 . _:b446299675 . _:b446299629 . _:b446299674 . _:b446299806 . _:b446299685 . . _:b446299684 . . _:b446299687 . . . _:b446299686 . . _:b446299558 . _:b446299681 . _:b446299680 . . _:b446299498 . _:b446299683 . _:b446299834 . _:b446299682 . . _:b446299693 . _:b446299692 . . _:b446299695 . . _:b446299765 . _:b446299694 . _:b446299689 . . _:b446299695 . _:b446299688 . . _:b446299802 . _:b446299691 . . _:b446299690 . _:b446299701 . _:b446299700 . _:b446299703 . _:b9111661 "methods" . _:b446299702 . _:b446299501 . _:b446299697 . _:b446299331 . _:b446299696 . _:b446299652 . _:b446299699 . . _:b446299403 . _:b446299698 . _:b9111680 "of the immune system is TGF-\u03B22, as it has multiple effects on immunoregulatory functions, including the inhibition of lymphokine-activated killer cells and T-lymphocyte development and interleukin-2\u2013dependent growth of T cells.>>5<<,28\u201331 Thus, the transient reduction in TGF-\u03B22 levels via the antisense compound trabedersen may reverse TGF-\u03B22\u2013mediated immunosuppression." . _:b446299709 . _:b446299963 . _:b446299708 . . _:b446299711 . _:b446299710 . _:b446299705 . . _:b446299704 . _:b446299941 . _:b446299667 . _:b446299707 . _:b446299706 . . _:b446299717 . . . _:b446299716 . . _:b446299719 . _:b446299718 . _:b446299847 . _:b446299812 . _:b446299713 . _:b446299694 . _:b446299540 . _:b446299342 . _:b446299712 . _:b446299895 . _:b446299715 . _:b446299714 . _:b446299725 . . . _:b446299724 . _:b446299727 . _:b446299755 . _:b446299726 . . _:b446299721 . _:b446299326 . . _:b446299720 . . _:b446299723 . _:b446299715 . _:b446299722 . _:b446299616 . . _:b446299733 . _:b446299710 . . _:b446299434 . _:b446299917 . _:b446299732 . . _:b446299735 . . _:b446299734 . _:b446299294 . _:b446299729 . _:b446299918 . . _:b446299728 . _:b446299731 . . _:b446299730 . . . _:b446299292 . _:b446299741 . _:b446299740 . _:b446299747 . _:b446299929 . _:b446299571 . _:b446299842 . _:b446299743 . _:b446299795 . . . _:b446299742 . . . _:b446299514 . _:b446299737 . _:b446299736 . _:b446299980 . _:b446299591 . _:b446299348 . _:b446299739 . . _:b446299738 . _:b446299749 . _:b446299582 . . _:b446299392 . _:b446299748 . _:b446299751 . _:b446299934 . _:b446299750 . . _:b446299745 . . _:b446299744 . _:b446299517 . _:b446299470 . _:b446299747 . . _:b446299746 . _:b446299494 . _:b446299757 . . . _:b446299756 . _:b446299699 . _:b446299759 . _:b446299301 . _:b446299987 . _:b446299758 . _:b446299759 . _:b446299905 . _:b446299753 . . . _:b446299752 . _:b446299755 . _:b446299754 . . _:b446299765 . . _:b446299968 . _:b446299442 . . _:b446299764 . _:b446299767 . _:b446299766 . . _:b446299815 . _:b446299761 . _:b446299945 . _:b446299760 . . _:b446299763 . _:b446299762 . . . _:b446299773 . _:b446299772 . _:b446299464 . _:b446299775 . _:b446299734 . _:b446299774 . . _:b446299408 . . . . _:b446299769 . _:b446299920 . _:b446299768 . . _:b446299771 . _:b446299770 . . _:b446299790 . _:b446299781 . . _:b446299780 . . _:b446299783 . _:b446299610 . _:b446299544 . _:b446299782 . _:b446299777 . . _:b446299776 . _:b446299779 . . _:b446299805 . _:b446299778 . . _:b446299789 . . . _:b446299788 . _:b446299791 . . _:b446299754 . . _:b446299790 . _:b446299288 . _:b446299654 . _:b446299785 . . . . _:b446299784 . . . . _:b446299595 . _:b446299336 . _:b446299787 . _:b446299736 . _:b446299786 . _:b446299797 . _:b446299796 . . _:b446299799 . _:b446299948 . . _:b446299798 . . _:b446299903 . _:b446299295 . _:b446299793 . _:b446299539 . . _:b446299792 . _:b446299795 . _:b446299885 . _:b446299794 . . _:b446299805 . _:b446299804 . _:b446299807 . . _:b446299806 . . _:b446299801 . _:b446299800 . . _:b446299803 . . . _:b446299802 . . _:b446299813 . _:b446299837 . . _:b446299812 . _:b446299883 . _:b446299815 . _:b446299436 . _:b446299814 . _:b9111671 "standard\u201D endpoint for oncology trials.21,22 However, it has turned out in recent years that this may not be appropriate for therapies that have a completely different mode of action from fast-acting cytotoxic or cytoreductive agents.22,>>23<< This particularly applies to immuno-based therapies, such as trabedersen, which rely on building an immune response over time." . _:b446299809 . . _:b446299808 . _:b446299936 . _:b446299577 . _:b446299811 . . . _:b446299810 . _:b446299555 . . _:b446299821 . _:b446299653 "2"^^ . _:b446299665 . _:b446299820 . _:b446299652 "2"^^ . _:b446299823 . _:b446299655 "2"^^ . _:b446299822 . _:b446299654 "2"^^ . _:b446299817 . _:b446299649 "2"^^ . _:b446299313 . _:b446299816 . _:b446299648 "2"^^ . _:b446299819 . _:b446299879 . _:b446299651 "2"^^ . _:b446299572 . _:b446299818 . . _:b446299650 "2"^^ . _:b446299914 . _:b446299981 . . _:b446299829 . _:b446299661 "2"^^ . _:b446299828 . _:b446299660 "2"^^ . . _:b446299831 . _:b446299663 "2"^^ . _:b446299830 . . _:b446299662 "2"^^ . . _:b446299825 . _:b446299657 "2"^^ . _:b446299803 . _:b446299824 . _:b446299656 "2"^^ . . _:b446299827 . _:b446299659 "2"^^ . _:b446299287 . _:b446299826 . _:b446299763 . _:b446299658 "2"^^ . . _:b446299837 . _:b446299669 "2"^^ . _:b446299708 . _:b446299394 . . _:b446299836 . . _:b446299668 "2"^^ . _:b446299839 . _:b9111684 . _:b446299671 "2"^^ . . _:b446299838 . _:b446299334 . . _:b446299538 . _:b446299670 "2"^^ . _:b446299833 . _:b9111669 "not show statistically significant differences among the treatment groups. Endpoints based on tumor assessments early after treatment start are recognized surrogate endpoints for OS, the \u201Cgold standard\u201D endpoint for oncology trials.21,>>22<< However, it has turned out in recent years that this may not be appropriate for therapies that have a completely different mode of action from fast-acting cytotoxic or cytoreductive agents." . _:b446299665 "2"^^ . _:b446299832 . _:b446299664 "2"^^ . . _:b446299835 . _:b446299667 "2"^^ . . _:b446299834 . _:b9111674 "An increase in tumor response over time for trabedersen had already been observed in phase I/II studies,>>12<< where 2 patients had long-lasting complete tumor remissions appearing several months after initiation of treatment." . _:b446299666 "2"^^ . . _:b446299845 . . _:b446299677 "2"^^ . _:b446299844 . _:b446299676 "2"^^ . . _:b446299847 . _:b446299679 "2"^^ . "10.1093%2Fneuonc%2Fnoq142" . _:b446299846 . _:b446299575 . _:b446299678 "2"^^ . _:b446299876 . _:b446299841 . _:b446299673 "2"^^ . _:b446299749 . _:b446299840 . _:b446299672 "2"^^ . _:b446299843 . _:b446299675 "2"^^ . . _:b446299842 . _:b446299674 "2"^^ . . _:b446299927 . _:b446299853 . _:b446299685 "2"^^ . _:b446299509 . . _:b446299852 . _:b446299684 "2"^^ . _:b446299855 . _:b446299687 "2"^^ . _:b446299692 . _:b446299854 . _:b446299686 "2"^^ . _:b446299849 . _:b446299681 "2"^^ . _:b446299445 . . _:b446299848 . _:b446299680 "2"^^ . . _:b446299324 . _:b446299376 . _:b446299851 . _:b446299427 . _:b446299824 . _:b446299683 "2"^^ . _:b446299850 . _:b446299682 "2"^^ . _:b446299785 . _:b446299861 . _:b446299693 "2"^^ . . . _:b446299860 . _:b446299692 "2"^^ . . _:b446299863 . . _:b446299695 "2"^^ . _:b446299862 . _:b446299694 "2"^^ . _:b9111666 . _:b446299647 . _:b446299521 . _:b446299857 . _:b446299689 "2"^^ . _:b446299949 . _:b446299856 . _:b446299688 "2"^^ . _:b446299363 . _:b446299859 . _:b446299691 "2"^^ . _:b446299858 . _:b446299690 "2"^^ . _:b446299869 . _:b446299701 "2"^^ . _:b446299773 . _:b446299868 . _:b446299700 "2"^^ . _:b446299871 . . _:b446299703 "2"^^ . _:b446299977 . _:b446299870 . . _:b446299702 "2"^^ . _:b446299398 . _:b446299865 . _:b446299697 "2"^^ . . _:b446299864 . _:b446299696 "2"^^ . _:b446299867 . _:b446299699 "2"^^ . _:b446299866 . _:b446299897 . _:b446299698 "2"^^ . _:b446299877 . . _:b446299709 "2"^^ . _:b446299876 . . _:b446299708 "2"^^ . _:b446299879 . . _:b446299711 "2"^^ . _:b446299758 . _:b446299878 . . _:b446299710 "2"^^ . _:b446299867 . . _:b446299873 . _:b446299570 . . _:b446299705 "2"^^ . _:b446299851 . _:b446299872 . _:b446299704 "2"^^ . _:b9111677 . _:b446299875 . . . _:b446299707 "2"^^ . _:b446299874 . . _:b446299706 "2"^^ . _:b446299885 . _:b446299327 . _:b446299717 "2"^^ . _:b446299884 . _:b446299779 . _:b446299716 "2"^^ . _:b446299648 . _:b446299887 . _:b446299825 . _:b446299719 "2"^^ . . . _:b446299886 . . _:b446299718 "2"^^ . _:b446299286 . _:b446299881 . _:b446299713 "2"^^ . . _:b446299880 . . _:b446299712 "2"^^ . _:b446299883 . _:b446299715 "2"^^ . . _:b9111681 . . _:b446299882 . _:b446299714 "2"^^ . _:b446299967 . _:b446299657 . _:b446299893 . _:b446299725 "2"^^ . _:b9111684 "In these patients, pseudoprogression was associated with a favorable survival (manuscript in preparation), as has been reported previously in high-grade glioma patients treated with radiotherapy and TMZ.>>33<<" . . _:b446299892 . _:b446299724 "2"^^ . _:b446299798 . . _:b446299895 . . _:b446299727 "2"^^ . . _:b446299894 . _:b446299726 "2"^^ . _:b446299982 . _:b446299332 . _:b446299889 . _:b446299721 "2"^^ . _:b446299888 . _:b446299720 "2"^^ . _:b9111681 . _:b446299954 . . . _:b446299891 . _:b446299723 "2"^^ . _:b446299890 . _:b446299722 "2"^^ . _:b446299901 . _:b446299733 "2"^^ . _:b446299686 . _:b446299900 . _:b446299732 "2"^^ . . _:b446299903 . _:b446299735 "2"^^ . _:b446299902 . . _:b446299734 "2"^^ . _:b446299897 . . _:b446299729 "2"^^ . _:b446299896 . _:b446299728 "2"^^ . . . _:b446299899 . _:b446299731 "2"^^ . _:b446299898 . _:b446299372 . . _:b446299730 "2"^^ . _:b446299666 . _:b446299397 . _:b446299741 "2"^^ . _:b446299396 . _:b446299740 "2"^^ . _:b446299569 . _:b446299399 . _:b446299743 "2"^^ . . _:b446299398 . _:b446299742 "2"^^ . _:b446299393 . _:b446299737 "2"^^ . . _:b446299392 . . _:b446299736 "2"^^ . . _:b446299395 . _:b446299739 "2"^^ . _:b446299394 . . _:b446299738 "2"^^ . . _:b446299405 . _:b446299878 . _:b446299524 . . _:b446299749 "2"^^ . _:b446299404 . . _:b446299748 "2"^^ . _:b446299407 . _:b446299751 "2"^^ . _:b9111660 "Furthermore, as it is well known that high-grade glioma patients with lower age and higher KPS have a better prognosis,18,>>20<< an additional exploratory analysis was performed for GBM patients with the prespecified prognostic factors age \u226455 years and KPS >80%." . _:b446299406 . _:b446299721 . _:b446299817 . _:b446299750 "2"^^ . . _:b446299401 . _:b446299745 "2"^^ . _:b446299400 . _:b446299744 "2"^^ . _:b446299403 . _:b446299747 "2"^^ . _:b446299402 . _:b446299746 "2"^^ . _:b446299413 . . _:b446299757 "2"^^ . _:b446299845 . _:b446299412 . _:b446299756 "2"^^ . _:b446299458 . _:b446299415 . _:b446299759 "2"^^ . _:b446299414 . . . _:b446299758 "2"^^ . _:b446299409 . _:b446299880 . . _:b446299753 "2"^^ . _:b446299408 . _:b9111682 "All these tumor lesions receded completely after local therapy of only 1 tumor lesion with trabedersen.>>12<< This phenomenon was also observed in patients of this phase IIb study." . _:b446299752 "2"^^ . _:b446299411 . _:b446299755 "2"^^ . _:b446299698 . _:b446299410 . _:b446299754 "2"^^ . _:b446299421 . _:b446299765 "2"^^ . . _:b446299420 . . _:b446299764 "2"^^ . _:b446299781 . _:b446299620 . _:b446299423 . _:b446299767 "2"^^ . _:b446299422 . . . _:b446299766 "2"^^ . _:b446299417 . _:b446299761 "2"^^ . _:b446299416 . _:b446299760 "2"^^ . . _:b446299419 . _:b446299829 . _:b446299771 . _:b446299417 . _:b446299763 "2"^^ . _:b446299418 . _:b446299762 "2"^^ . _:b446299938 . _:b446299664 . . _:b446299429 . _:b446299773 "2"^^ . _:b446299428 . _:b446299772 "2"^^ . _:b446299896 . _:b446299431 . _:b446299640 . _:b446299775 "2"^^ . _:b446299430 . _:b446299774 "2"^^ . _:b446299425 . _:b446299769 "2"^^ . _:b446299424 . _:b446299768 "2"^^ . _:b446299427 . _:b446299438 . _:b446299771 "2"^^ . _:b446299426 . _:b446299770 "2"^^ . _:b446299437 . _:b446299781 "2"^^ . _:b446299965 . _:b446299330 . _:b446299436 . _:b446299780 "2"^^ . _:b446299439 . _:b446299783 "2"^^ . . _:b446299438 . _:b446299782 "2"^^ . _:b446299433 . _:b446299777 "2"^^ . _:b446299644 . . _:b446299432 . _:b446299776 "2"^^ . . _:b446299435 . _:b446299779 "2"^^ . _:b446299673 . _:b446299434 . _:b446299778 "2"^^ . _:b446299445 . _:b446299789 "2"^^ . _:b446299444 . _:b446299788 "2"^^ . _:b446299447 . _:b446299454 . _:b446299791 "2"^^ . _:b446299446 . _:b446299953 . . _:b446299790 "2"^^ . . _:b446299441 . _:b446299785 "2"^^ . _:b446299907 . _:b446299440 . _:b446299784 "2"^^ . _:b446299443 . _:b446299787 "2"^^ . _:b446299889 . . _:b446299442 . _:b446299786 "2"^^ . _:b446299453 . . _:b446299797 "2"^^ . _:b446299703 . _:b446299452 . _:b446299796 "2"^^ . _:b446299455 . _:b446299799 "2"^^ . _:b446299454 . . _:b446299798 "2"^^ . _:b446299449 . _:b446299793 "2"^^ . _:b446299448 . . _:b446299792 "2"^^ . _:b446299451 . _:b446299795 "2"^^ . _:b446299450 . _:b446299794 "2"^^ . . _:b446299461 . _:b446299805 "2"^^ . _:b446299431 . _:b446299460 . _:b446299846 . _:b446299804 "2"^^ . _:b446299463 . . _:b446299807 "2"^^ . . _:b446299462 . . _:b9111667 "discussion" . _:b446299806 "2"^^ . _:b446299457 . . _:b446299801 "2"^^ . _:b446299456 . . _:b446299800 "2"^^ . _:b446299459 . _:b446299803 "2"^^ . _:b446299458 . _:b446299615 . _:b446299802 "2"^^ . _:b446299469 . _:b446299813 "2"^^ . _:b446299468 . _:b446299812 "2"^^ . _:b446299471 . . _:b446299815 "2"^^ . . _:b446299560 . _:b446299916 . _:b446299680 . _:b446299470 . _:b446299814 "2"^^ . _:b446299465 . . _:b446299809 "2"^^ . _:b446299388 . _:b446299464 . . _:b446299808 "2"^^ . _:b446299599 . _:b446299919 . _:b446299467 . . _:b446299811 "2"^^ . _:b446299486 . _:b446299466 . _:b446299810 "2"^^ . _:b446299477 . . . _:b446299821 "2"^^ . . _:b446299476 . . _:b446299820 "2"^^ . _:b446299479 . . _:b446299823 "2"^^ . _:b9111660 . _:b446299478 . _:b446299822 "2"^^ . _:b9111661 . _:b446299473 . _:b446299817 "2"^^ . _:b9111662 . _:b446299472 . . . _:b446299742 . _:b446299816 "2"^^ . _:b9111663 . _:b446299475 . . _:b446299819 "2"^^ . _:b9111656 . _:b446299784 . _:b446299474 . _:b446299529 . _:b446299559 . _:b9111657 . _:b446299818 "2"^^ . _:b446299485 . _:b446299829 "2"^^ . _:b9111658 . _:b446299738 . _:b446299484 . . _:b446299828 "2"^^ . _:b9111659 . . . _:b446299487 . _:b446299831 "2"^^ . _:b9111668 . _:b446299322 . _:b446299486 . . _:b446299830 "2"^^ . _:b9111669 . _:b446299481 . . _:b446299825 "2"^^ . _:b9111670 . _:b446299480 . _:b446299346 . _:b446299824 "2"^^ . _:b9111671 . _:b446299314 . _:b446299483 . _:b446299712 . _:b446299827 "2"^^ . _:b9111664 . _:b446299482 . _:b446299826 "2"^^ . _:b9111665 . _:b446299493 . _:b446299837 "2"^^ . _:b9111666 . _:b446299492 . _:b446299836 "2"^^ . _:b9111667 . _:b446299495 . . _:b446299839 "2"^^ . _:b9111676 . _:b446299494 . _:b446299838 "2"^^ . _:b9111677 . _:b446299489 . _:b446299833 "2"^^ . _:b9111678 . _:b446299488 . _:b446299832 "2"^^ . _:b9111679 . _:b446299491 . _:b446299835 "2"^^ . _:b9111672 . _:b446299490 . _:b446299834 "2"^^ . _:b9111673 . . _:b446299501 . _:b446299845 "2"^^ . _:b9111674 . . _:b446299500 . _:b446299844 "2"^^ . _:b9111675 . _:b446299589 . _:b446299503 . _:b446299847 "2"^^ . _:b9111684 . _:b446299476 . . _:b446299502 . . _:b446299846 "2"^^ . _:b446299714 . _:b446299497 . _:b446299465 . _:b446299841 "2"^^ . _:b446299496 . . _:b446299840 "2"^^ . _:b446299499 . _:b446299843 "2"^^ . _:b9111680 . _:b446299498 . _:b446299842 "2"^^ . _:b9111681 . . . _:b446299509 . _:b446299471 . _:b9111682 . _:b446299853 "2"^^ . _:b446299561 . _:b446299565 . _:b446299508 . _:b446299887 . _:b446299852 "2"^^ . _:b9111683 . _:b446299511 . _:b446299906 . _:b446299855 "2"^^ . _:b446299510 . _:b446299854 "2"^^ . . _:b446299505 . _:b446299849 "2"^^ . . _:b446299504 . _:b446299848 "2"^^ . . _:b446299507 . _:b446299472 . _:b446299851 "2"^^ . _:b446299506 . _:b446299850 "2"^^ . . _:b446299517 . _:b446299573 . _:b446299861 "2"^^ . _:b446299516 . _:b446299584 . _:b446299811 . _:b446299860 "2"^^ . _:b446299519 . _:b446299863 "2"^^ . _:b446299518 . _:b446299862 "2"^^ . _:b446299513 . _:b446299857 "2"^^ . _:b446299512 . . _:b446299856 "2"^^ . _:b446299515 . _:b9111681 . _:b446299859 "2"^^ . . _:b446299514 . _:b446299858 "2"^^ . _:b446299525 . _:b446299869 "2"^^ . _:b446299524 . _:b446299868 "2"^^ . _:b446299527 . . _:b446299871 "2"^^ . _:b446299526 . _:b9111665 "13,14 In contrast to other CED studies,15,>>16<< a single catheter was placed into the solid and contrast-enhancing area of the largest tumor lesion." . _:b446299870 "2"^^ . _:b446299521 . _:b446299407 . _:b446299865 "2"^^ . . _:b446299453 . _:b446299520 . _:b446299864 "2"^^ . . _:b446299523 . _:b446299867 "2"^^ . _:b446299835 . _:b446299522 . _:b446299866 "2"^^ . _:b446299533 . _:b446299877 "2"^^ . . _:b446299682 . _:b446299468 . _:b446299532 . _:b446299876 "2"^^ . _:b446299535 . _:b446299879 "2"^^ . . . _:b446299909 . _:b446299534 . . _:b446299878 "2"^^ . _:b446299804 . _:b446299529 . _:b446299873 "2"^^ . . _:b446299528 . _:b446299872 "2"^^ . _:b446299531 . . _:b446299875 "2"^^ . _:b446299530 . _:b446299461 . _:b446299683 . _:b446299944 . _:b446299874 "2"^^ . _:b446299541 . _:b446299940 . . . _:b446299369 . _:b446299885 "2"^^ . _:b446299540 . _:b446299884 "2"^^ . . _:b446299979 . _:b446299543 . _:b446299387 . _:b446299887 "2"^^ . _:b446299542 . _:b446299886 "2"^^ . _:b446299537 . _:b446299881 "2"^^ . . . _:b446299536 . _:b446299623 . . _:b446299880 "2"^^ . _:b446299539 . _:b446299397 . _:b446299883 "2"^^ . _:b446299538 . _:b446299882 "2"^^ . _:b446299549 . _:b446299893 "2"^^ . _:b446299548 . _:b446299892 "2"^^ . . . _:b446299551 . _:b446299895 "2"^^ . _:b446299655 . . _:b446299550 . . _:b446299894 "2"^^ . . _:b446299492 . _:b446299545 . _:b446299889 "2"^^ . _:b446299544 . _:b446299888 "2"^^ . _:b446299668 . _:b446299547 . _:b446299289 . . _:b446299891 "2"^^ . _:b446299546 . _:b446299890 "2"^^ . _:b446299931 . . _:b446299557 . _:b446299901 "2"^^ . _:b446299556 . _:b446299787 . _:b446299973 . _:b446299900 "2"^^ . _:b446299559 . _:b446299903 "2"^^ . _:b446299558 . _:b446299479 . _:b446299902 "2"^^ . . _:b446299892 . _:b446299797 . _:b446299553 . _:b446299897 "2"^^ . . . _:b446299552 . _:b446299896 "2"^^ . _:b446299555 . . _:b446299899 "2"^^ . _:b446299554 . _:b446299469 . _:b446299898 "2"^^ . _:b446299724 . _:b446299565 . _:b446299515 . _:b446299456 . _:b446299909 "2"^^ . _:b446299564 . _:b446299428 . _:b446299908 "2"^^ . _:b446299437 . _:b446299567 . . _:b446299911 "2"^^ . _:b446299566 . . _:b446299910 "2"^^ . . _:b446299561 . _:b446299905 "2"^^ . _:b446299560 . _:b446299593 . _:b446299904 "2"^^ . _:b446299563 . _:b446299907 "2"^^ . _:b446299656 . _:b446299562 . _:b446299906 "2"^^ . . _:b446299573 . _:b446299917 "2"^^ . _:b446299605 . _:b446299572 . . _:b446299916 "2"^^ . _:b446299341 . . _:b446299575 . _:b446299919 "2"^^ . _:b446299563 . _:b446299574 . _:b446299918 "2"^^ . _:b446299569 . _:b446299913 "2"^^ . _:b446299568 . _:b446299943 . _:b446299912 "2"^^ . . . . _:b446299571 . . . _:b446299462 . _:b446299915 "2"^^ . _:b446299570 . _:b446299914 "2"^^ . _:b446299581 . _:b446299925 "2"^^ . _:b446299395 . _:b446299958 . _:b446299580 . . _:b446299924 "2"^^ . . _:b446299603 . _:b446299583 . _:b446299927 "2"^^ . _:b446299709 . _:b446299582 . _:b446299926 "2"^^ . _:b446299333 . _:b446299577 . _:b446299921 "2"^^ . _:b446299576 . _:b446299633 . _:b446299396 . _:b446299920 "2"^^ . _:b446299579 . _:b446299872 . . _:b446299923 "2"^^ . _:b446299578 . _:b446299922 "2"^^ . _:b9111663 "via a subcutaneous port access system connected to an external pump allowing outpatient treatment. The CED technique allows a highly efficient, homogeneous, and targeted administration of the drug, bypassing the blood\u2013brain barrier.13,>>14<< In contrast to other CED studies,15,16 a single catheter was placed into the solid and contrast-enhancing area of the largest tumor lesion." . _:b446299589 . _:b9111661 _:b9111664 . _:b446299933 "2"^^ . _:b9111661 _:b9111665 . _:b446299435 . _:b9111661 _:b9111666 . _:b446299588 . _:b446299932 "2"^^ . _:b9111672 "22,23 This particularly applies to immuno-based therapies, such as trabedersen, which rely on building an immune response over time.>>23<<,24 Indeed, the results of this study show that the clinically relevant beneficial effect of trabedersen increases over time, which was visible especially in the 10 \u00B5M trabedersen group and was most evident at 14 months regarding tumor" . _:b446299591 . _:b9111656 _:b9111660 . _:b446299935 "2"^^ . _:b446299590 . . _:b446299934 "2"^^ . _:b9111656 _:b9111657 . _:b9111656 _:b9111658 . _:b446299585 . _:b9111656 _:b9111659 . _:b446299929 "2"^^ . _:b446299455 . _:b446299584 . . _:b446299928 "2"^^ . _:b446299587 . . _:b446299354 . _:b446299931 "2"^^ . _:b446299586 . _:b446299930 "2"^^ . _:b9111661 _:b9111662 . _:b446299950 . _:b446299597 . _:b9111661 _:b9111663 . _:b446299941 "2"^^ . _:b446299596 . _:b446299298 . _:b446299921 . _:b446299822 . _:b446299940 "2"^^ . _:b446299599 . _:b446299807 . _:b446299928 . _:b446299943 "2"^^ . _:b446299969 . _:b446299598 . _:b446299862 . _:b446299942 "2"^^ . _:b446299386 . _:b446299593 . . _:b9111667 _:b9111672 . _:b446299937 "2"^^ . _:b9111667 _:b9111673 . . _:b446299592 . _:b9111667 _:b9111674 . _:b9111667 _:b9111675 . _:b9111667 _:b9111676 . _:b446299936 "2"^^ . _:b9111667 _:b9111677 . _:b9111667 _:b9111678 . _:b446299595 . _:b9111667 _:b9111679 . _:b446299345 . _:b446299939 "2"^^ . _:b446299594 . _:b9111667 _:b9111668 . _:b446299938 "2"^^ . _:b446299487 . _:b9111667 _:b9111669 . _:b9111667 _:b9111670 . _:b446299605 . _:b9111667 _:b9111671 . _:b446299949 "2"^^ . _:b446299604 . _:b446299731 . . _:b446299948 "2"^^ . _:b446299607 . _:b446299844 . _:b446299951 "2"^^ . _:b446299606 . _:b446299950 "2"^^ . _:b446299601 . _:b446299945 "2"^^ . _:b446299562 . _:b446299600 . _:b446299944 "2"^^ . _:b446299393 . . _:b446299603 . _:b446299947 "2"^^ . _:b446299602 . . _:b446299946 "2"^^ . _:b446299799 . _:b446299613 . _:b446299600 . _:b446299957 "2"^^ . _:b446299557 . _:b446299612 . . _:b446299956 "2"^^ . _:b446299615 . . _:b446299959 "2"^^ . . _:b446299614 . _:b446299871 . _:b446299962 . _:b446299958 "2"^^ . _:b446299609 . . _:b446299953 "2"^^ . _:b446299608 . _:b446299952 "2"^^ . . _:b446299611 . _:b446299955 "2"^^ . _:b446299433 . _:b446299513 . _:b446299610 . _:b446299816 . _:b446299954 "2"^^ . _:b446299621 . _:b446299688 . _:b446299965 "2"^^ . _:b446299620 . _:b446299964 "2"^^ . _:b446299622 . _:b446299623 . . _:b9111667 _:b9111680 . _:b446299967 "2"^^ . _:b446299863 . _:b9111667 _:b9111681 . _:b9111667 _:b9111682 . _:b446299622 . _:b9111667 _:b9111683 . _:b9111667 _:b9111684 . _:b446299966 "2"^^ . _:b446299337 . _:b446299617 . . . _:b446299961 "2"^^ . _:b446299616 . _:b446299960 "2"^^ . _:b446299619 . . _:b446299963 "2"^^ . . _:b446299618 . _:b446299900 . . _:b446299962 "2"^^ . _:b446299629 . . _:b446299973 "2"^^ . _:b446299523 . _:b446299628 . _:b446299972 "2"^^ . _:b446299631 . _:b446299975 "2"^^ . _:b446299630 . _:b446299335 . _:b446299974 "2"^^ . _:b446299625 . _:b446299530 . _:b446299969 "2"^^ . _:b446299624 . _:b446299968 "2"^^ . _:b446299627 . . _:b446299971 "2"^^ . _:b446299626 . _:b446299970 "2"^^ . _:b446299637 . _:b446299981 "2"^^ . _:b446299636 . _:b446299980 "2"^^ . . _:b446299639 . _:b446299368 . . _:b446299983 "2"^^ . _:b446299638 . _:b446299982 "2"^^ . . _:b446299633 . _:b446299977 "2"^^ . _:b446299632 . _:b9111658 . _:b446299592 . . _:b446299976 "2"^^ . _:b446299635 . _:b446299482 . _:b446299979 "2"^^ . _:b446299634 . . . . _:b446299978 "2"^^ . _:b446299645 . . _:b446299854 . _:b446299644 . _:b446299588 . _:b446299647 . . _:b446299646 . _:b446299641 . . _:b446299922 . _:b446299985 "2"^^ . _:b446299640 . _:b446299821 . _:b446299535 . _:b446299984 "2"^^ . _:b446299643 . _:b446299987 "2"^^ . . . _:b446299642 . _:b446299986 "2"^^ . . _:b446299598 . _:b446299741 . . . _:b9111683 . . _:b446299628 . _:b9111666 "trabedersen groups were compared descriptively with the standard chemotherapy group. Tumor assessments were done via central, blinded MRI readings of 2 independent radiologists and 1 adjudicator using the classical Macdonald criteria.>>17<< The tumor control rate was defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD)." . _:b446299489 . . _:b446299857 . . _:b9111662 . . _:b446299553 . _:b446299668 . . _:b446299669 . _:b446299670 . _:b446299671 . _:b446299664 . _:b9111661 . _:b446299315 . _:b446299665 . _:b446299666 . _:b446299667 . _:b9111656 . _:b446299347 . _:b446299676 . _:b446299677 . _:b446299678 . _:b446299679 . _:b446299672 . _:b446299673 . _:b446299674 . _:b446299675 . . _:b446299652 . _:b446299653 . _:b446299654 . _:b9111667 . . . _:b446299655 . _:b446299648 . _:b446299649 . _:b446299650 . _:b446299651 . _:b446299660 . _:b446299661 . _:b446299662 . _:b446299663 . _:b446299656 . . _:b446299657 . _:b446299658 . _:b446299659 . _:b9111668 "did not show statistically significant differences among the treatment groups. Endpoints based on tumor assessments early after treatment start are recognized surrogate endpoints for OS, the \u201Cgold standard\u201D endpoint for oncology trials.>>21<<,22 However, it has turned out in recent years that this may not be appropriate for therapies that have a completely different mode of action from fast-acting cytotoxic or cytoreductive agents." . _:b446299700 . _:b446299701 . . . _:b446299702 . _:b446299703 . _:b446299311 . _:b446299696 . . _:b446299697 . . _:b446299698 . _:b446299440 . _:b446299932 . . _:b446299699 . _:b446299389 . _:b446299708 . _:b446299709 . _:b446299710 . _:b446299711 . _:b446299704 . _:b446299705 . _:b446299706 . . _:b446299707 . _:b446299684 . _:b446299685 . _:b446299686 . . . _:b446299687 . _:b446299680 . _:b446299681 . _:b446299682 . _:b446299683 . . _:b446299692 . _:b446299693 . _:b446299694 . . _:b446299695 . _:b446299688 . _:b446299689 . _:b446299690 . . _:b446299691 . _:b446299732 . _:b446299733 . _:b446299734 . _:b446299735 . _:b446299728 . _:b446299729 . _:b446299730 . _:b446299690 . _:b446299731 . _:b446299740 . . _:b446299741 . _:b446299742 . _:b446299743 . _:b446299736 . _:b446299737 . . _:b446299738 . _:b446299739 . _:b446299716 . _:b446299717 . . _:b446299718 . _:b446299719 . _:b446299712 . _:b446299713 . _:b446299819 . _:b446299714 . _:b446299715 . _:b446299724 . _:b446299725 . _:b446299939 . _:b446299726 . _:b446299727 . _:b446299720 . . _:b446299721 . _:b446299722 . _:b446299723 . . _:b446299764 . . _:b446299765 . _:b446299766 . _:b446299767 . _:b446299760 . _:b446299761 . _:b446299762 . _:b446299763 . _:b446299483 . _:b446299772 . _:b9111659 "Furthermore, as it is well known that high-grade glioma patients with lower age and higher KPS have a better prognosis,>>18<<,20 an additional exploratory analysis was performed for GBM patients with the prespecified prognostic factors age \u226455 years and KPS >80%." . _:b446299773 . _:b446299774 . _:b446299775 . _:b446299768 . _:b446299769 . _:b446299770 . _:b446299447 . _:b446299771 . _:b446299748 . _:b446299870 . _:b446299749 . _:b446299597 . _:b446299901 . _:b446299750 . _:b446299751 . _:b446299744 . _:b446299745 . _:b446299746 . _:b446299747 . _:b446299756 . _:b446299757 . _:b446299758 . _:b446299759 . _:b446299752 . _:b446299753 . . _:b446299663 . _:b446299754 . _:b446299755 . _:b446299796 . . _:b446299797 . _:b446299757 . . _:b446299798 . _:b446299799 . _:b446299792 . _:b446299793 . _:b446299459 . _:b446299794 . . _:b446299795 . . _:b446299886 . . _:b446299804 . _:b446299805 . _:b446299888 . _:b446299806 . _:b446299807 . _:b446299800 . _:b446299801 . _:b446299802 . _:b446299803 . _:b446299780 . _:b446299781 . _:b446299782 . _:b446299783 . _:b446299776 . _:b446299717 . _:b446299777 . _:b446299778 . _:b446299779 . _:b446299485 . _:b446299788 . . . _:b446299789 . _:b446299790 . _:b446299791 . _:b446299784 . . _:b446299853 . _:b446299785 . _:b446299786 . _:b446299787 . _:b446299828 . _:b446299829 . _:b446299830 . _:b446299831 . . _:b446299824 . _:b446299825 . _:b446299826 . _:b446299827 . _:b446299836 . . _:b446299837 . . _:b446299838 . _:b446299839 . _:b446299832 . _:b446299833 . _:b446299834 . _:b446299835 . _:b446299812 . _:b446299813 . . _:b446299814 . _:b446299815 . _:b446299808 . _:b446299809 . . _:b446299810 . _:b446299414 . _:b446299811 . _:b446299820 . _:b446299821 . . _:b446299822 . _:b446299823 . _:b446299816 . _:b446299817 . _:b446299818 . _:b446299819 . . _:b446299860 . _:b446299861 . _:b446299862 . _:b446299658 . _:b446299511 . _:b446299863 . _:b446299856 . _:b446299857 . _:b446299858 . _:b446299859 . _:b446299868 . . _:b446299869 . _:b446299870 . _:b446299871 . _:b446299864 . _:b446299551 . _:b446299865 . _:b446299866 . _:b446299867 . _:b446299844 . _:b446299845 . _:b446299846 . _:b446299847 . _:b9111660 . _:b446299840 . _:b446299841 . _:b446299842 . _:b446299843 . _:b446299852 . _:b446299853 . _:b446299854 . _:b446299855 . . _:b446299848 . _:b446299849 . _:b446299850 . _:b446299441 . _:b446299851 . _:b446299892 . _:b446299893 . . _:b446299894 . _:b446299594 . _:b446299895 . _:b446299888 . . _:b446299889 . _:b446299890 . _:b446299891 . _:b446299900 . _:b446299901 . _:b446299902 . _:b446299903 . _:b446299896 . _:b446299897 . _:b446299898 . _:b446299899 . _:b446299876 . _:b446299983 . _:b446299877 . _:b446299878 . _:b446299879 . _:b446299872 . _:b446299873 . _:b446299874 . _:b446299590 . _:b446299875 . _:b446299884 . _:b446299885 . _:b446299886 . _:b446299887 . _:b446299880 . _:b446299881 . _:b446299882 . _:b446299883 . _:b446299924 . _:b446299952 . _:b446299925 . _:b446299926 . _:b9111662 "via a subcutaneous port access system connected to an external pump allowing outpatient treatment. The CED technique allows a highly efficient, homogeneous, and targeted administration of the drug, bypassing the blood\u2013brain barrier.>>13<<,14 In contrast to other CED studies,15,16 a single catheter was placed into the solid and contrast-enhancing area of the largest tumor lesion." . _:b446299927 . _:b446299920 . _:b446299580 . _:b446299921 . _:b446299922 . _:b446299923 . _:b446299932 . _:b446299933 . _:b446299934 . _:b446299935 . _:b446299928 . . _:b446299929 . _:b446299411 . _:b446299930 . _:b446299931 . _:b446299908 . _:b446299909 . . _:b446299910 . _:b446299290 . _:b446299911 . _:b446299904 . _:b446299905 . _:b446299906 . . _:b446299907 . _:b446299916 . _:b446299917 . _:b446299918 . _:b446299919 . _:b446299912 . _:b446299913 . _:b446299914 . _:b446299915 . _:b446299956 . _:b446299957 . _:b446299608 . _:b446299958 . _:b446299959 . _:b446299952 . _:b446299953 . _:b446299954 . _:b446299955 . _:b446299964 . . _:b446299965 . _:b446299966 . _:b446299967 . _:b446299960 . _:b446299961 . _:b446299297 . _:b446299962 . _:b446299963 . _:b446299718 . _:b446299940 . . _:b446299941 . _:b446299942 . . _:b446299943 . . _:b446299936 . _:b446299937 . . _:b446299938 . _:b446299939 . . _:b446299948 . _:b446299949 . _:b446299950 . _:b446299951 . . _:b446299944 . . _:b446299945 . _:b446299946 . _:b446299947 . _:b446299722 . . _:b446299984 . _:b446299985 . _:b446299986 . _:b446299770 . _:b446299987 . _:b446299769 . _:b446299533 . _:b446299299 . . . _:b446299972 . _:b446299351 . _:b446299973 . _:b446299974 . _:b446299975 . _:b446299968 . _:b446299969 . _:b446299739 . _:b446299970 . _:b446299971 . _:b446299980 . _:b446299310 . _:b446299981 . _:b446299982 . _:b446299983 . _:b446299976 . _:b446299977 . _:b446299978 . _:b446299979 . _:b446299911 . _:b446299484 . _:b446299744 . _:b446299832 . _:b446299674 . . . _:b446299972 . . . . . . . . _:b446299894 . _:b446299400 . _:b446299581 . _:b446299776 . _:b446299772 . . . . . . . . _:b446299507 . _:b446299617 . _:b446299503 . _:b446299791 . _:b446299866 . _:b446299613 . . _:b446299293 . _:b446299697 . _:b446299319 . _:b446299632 . _:b446299984 . _:b446299732 . . _:b446299636 . . _:b446299669 . . _:b446299367 . _:b9111681 "of the immune system is TGF-\u03B22, as it has multiple effects on immunoregulatory functions, including the inhibition of lymphokine-activated killer cells and T-lymphocyte development and interleukin-2\u2013dependent growth of T cells.5,>>28<<\u201331 Thus, the transient reduction in TGF-\u03B22 levels via the antisense compound trabedersen may reverse TGF-\u03B22\u2013mediated immunosuppression." . _:b446299745 . . . . . _:b446299285 . _:b446299287 . _:b446299490 . _:b446299377 . . . _:b446299286 . _:b446299823 . . _:b446299792 . _:b446299293 . . _:b446299292 . _:b446299295 . _:b446299294 . _:b446299289 . . _:b446299691 . _:b446299288 . _:b446299510 . . _:b446299291 . _:b446299355 . _:b446299290 . . _:b446299861 . _:b446299301 . . _:b446299300 . . . _:b446299410 . _:b446299303 . _:b446299302 . . _:b446299297 . _:b446299328 . _:b446299502 . _:b446299704 . _:b446299296 . . _:b446299841 . . _:b446299299 . . . _:b446299298 . . _:b446299634 . . _:b446299309 . . _:b446299609 . _:b446299836 . _:b446299308 . . _:b446299970 . _:b446299311 . . _:b446299310 . _:b446299621 . . _:b446299305 . _:b446299304 . . . _:b446299307 . . _:b446299306 . _:b446299285 . _:b446299286 . _:b446299287 . _:b446299317 . _:b446299317 . _:b446299316 . _:b446299292 . _:b446299293 . _:b446299294 . _:b446299295 . _:b446299319 . _:b446299288 . . _:b446299418 . _:b446299289 . . _:b446299290 . . _:b446299291 . _:b446299318 . . _:b446299313 . . _:b446299446 . _:b446299312 . _:b446299315 . _:b446299525 . _:b446299314 . _:b446299316 . . . _:b446299937 . _:b446299317 . _:b446299318 . _:b446299782 . _:b446299319 . _:b446299325 . _:b446299312 . . _:b446299313 . _:b446299314 . _:b446299315 . _:b446299324 . _:b446299352 . _:b446299324 . . _:b446299325 . _:b446299326 . . _:b446299327 . _:b446299327 . _:b446299624 . _:b446299320 . _:b446299321 . _:b446299322 . _:b446299323 . . _:b446299326 . _:b446299300 . _:b446299301 . _:b446299302 . _:b446299303 . _:b446299321 . _:b446299296 . _:b446299743 . . _:b446299642 . _:b446299297 . _:b446299618 . _:b446299298 . _:b446299299 . _:b446299320 . _:b446299308 . _:b446299309 . _:b446299310 . _:b446299311 . _:b446299323 . _:b446299304 . _:b446299305 . _:b446299306 . _:b446299307 . _:b446299322 . _:b446299348 . . _:b446299349 . _:b446299350 . _:b446299351 . _:b446299333 . _:b446299344 . _:b446299345 . _:b446299346 . _:b446299347 . _:b446299332 . _:b446299356 . _:b446299357 . _:b446299358 . _:b446299359 . _:b446299335 . _:b446299352 . _:b446299353 . . _:b446299354 . _:b446299355 . _:b446299334 . _:b446299332 . _:b446299333 . . _:b446299334 . _:b446299335 . _:b446299329 . _:b446299328 . . . _:b446299329 . _:b446299330 . _:b446299331 . _:b446299328 . _:b446299340 . _:b446299341 . _:b446299342 . _:b446299343 . _:b446299331 . _:b446299336 . _:b446299337 . _:b446299643 . _:b446299338 . _:b446299339 . _:b446299330 . _:b446299380 . _:b446299381 . _:b446299849 . _:b446299382 . _:b446299416 . _:b446299383 . _:b446299341 . _:b446299376 . _:b446299377 . _:b446299378 . _:b446299379 . _:b446299340 . _:b446299388 . _:b446299389 . _:b446299390 . _:b446299391 . _:b446299343 . _:b446299384 . _:b446299385 . _:b446299320 . _:b446299386 . _:b446299387 . _:b446299342 . _:b446299364 . _:b446299365 . _:b446299366 . _:b446299367 . _:b446299337 . _:b446299360 . _:b446299361 . _:b446299362 . _:b446299363 . . _:b446299372 . _:b446299336 . _:b446299373 . _:b446299852 . _:b446299374 . _:b446299375 . _:b446299339 . _:b446299368 . _:b446299369 . _:b446299370 . _:b446299371 . _:b446299338 . _:b446299412 . _:b446299413 . _:b446299414 . _:b446299415 . _:b446299349 . _:b446299408 . _:b446299409 . _:b446299410 . _:b446299411 . _:b446299348 . _:b446299420 . _:b446299421 . _:b9111676 "were taken from patients of the control group. Generally, the frequency and nature of the reported events were typical for patients with primary brain tumors who usually have a large number of accompanying neurological disorders.>>25<<,26 One reason for more neurological AEs observed in the trabedersen groups may be the mode of administration of trabedersen through CED (ie, the infusion process through an implanted catheter)." . _:b446299422 . . _:b446299423 . _:b446299351 . _:b446299416 . _:b446299417 . . _:b446299813 . _:b446299418 . _:b446299419 . _:b446299350 . _:b446299396 . _:b446299360 . _:b446299397 . _:b446299398 . _:b446299323 . _:b446299399 . _:b446299345 . _:b446299392 . _:b446299393 . _:b446299394 . _:b446299395 . _:b446299344 . _:b446299404 . _:b446299405 . _:b446299406 . _:b446299407 . _:b446299930 . _:b446299347 . _:b446299400 . _:b446299401 . _:b446299843 . _:b446299371 . _:b446299402 . _:b446299403 . _:b446299346 . _:b446299444 . _:b446299445 . _:b446299446 . . _:b446299447 . _:b446299357 . _:b446299440 . _:b446299477 . _:b446299441 . _:b446299442 . . _:b446299443 . _:b446299356 . _:b446299452 . . _:b446299453 . _:b446299454 . _:b446299455 . _:b446299359 . _:b446299448 . _:b446299449 . _:b446299450 . _:b446299451 . _:b446299358 . _:b446299428 . _:b446299429 . _:b446299430 . _:b446299520 . _:b446299431 . _:b446299353 . _:b446299424 . _:b446299425 . _:b446299426 . _:b446299961 . . _:b446299427 . _:b446299352 . _:b446299436 . _:b446299437 . _:b446299438 . _:b446299439 . _:b446299355 . _:b446299432 . . _:b446299433 . _:b446299434 . _:b446299435 . _:b446299354 . _:b446299476 . _:b446299477 . _:b446299478 . _:b446299479 . _:b446299365 . _:b446299472 . _:b446299716 . _:b446299473 . _:b446299474 . _:b446299475 . _:b446299364 . _:b446299484 . _:b446299485 . _:b446299486 . . _:b446299487 . _:b446299421 . _:b446299367 . _:b446299480 . _:b446299481 . _:b446299482 . _:b446299537 . _:b446299483 . _:b446299366 . _:b446299460 . _:b446299547 . _:b446299461 . _:b446299462 . _:b446299463 . _:b446299361 . _:b446299456 . _:b446299457 . _:b446299458 . _:b446299459 . _:b446299360 . _:b446299468 . _:b446299469 . _:b446299470 . _:b446299471 . _:b446299363 . _:b446299464 . _:b446299465 . . _:b446299466 . _:b446299746 . _:b446299467 . _:b446299627 . _:b446299362 . _:b446299508 . _:b446299509 . _:b446299650 . _:b446299510 . _:b446299511 . _:b446299373 . _:b446299504 . _:b446299505 . _:b446299506 . _:b446299507 . _:b446299372 . _:b446299516 . _:b446299517 . _:b446299518 . _:b446299946 . . _:b446299519 . _:b446299375 . _:b446299512 . _:b446299513 . _:b446299514 . _:b446299515 . _:b446299374 . _:b446299978 . _:b446299492 . _:b446299493 . _:b446299494 . _:b446299495 . _:b446299369 . _:b446299488 . _:b446299489 . . _:b446299490 . _:b446299491 . _:b446299368 . _:b446299500 . _:b446299501 . _:b446299502 . _:b446299503 . _:b446299371 . _:b446299864 . _:b446299496 . _:b446299497 . _:b446299638 . _:b9111658 "As AA and GBM patients differ in their prognoses,18,>>19<< efficacy analyses were repeated on an exploratory basis separately for the 2 subpopulations of AA and GBM patients." . _:b446299498 . . _:b446299499 . _:b446299370 . _:b446299540 . . _:b446299541 . _:b446299339 . _:b446299542 . _:b446299543 . _:b446299536 . _:b446299381 . _:b446299537 . _:b446299538 . _:b446299539 . _:b446299548 . _:b446299380 . _:b446299549 . . _:b446299550 . _:b446299551 . _:b446299544 . _:b446299383 . _:b446299545 . . _:b446299546 . _:b446299547 . _:b446299325 . _:b446299524 . _:b446299382 . _:b446299525 . _:b446299526 . _:b446299527 . _:b446299309 . _:b446299520 . . _:b446299377 . _:b446299521 . _:b446299522 . _:b446299523 . _:b446299532 . _:b446299376 . _:b446299533 . _:b446299534 . _:b446299808 . _:b446299535 . _:b446299528 . _:b446299379 . _:b446299529 . _:b446299530 . _:b446299531 . _:b446299572 . _:b446299378 . _:b446299573 . _:b446299574 . _:b446299575 . _:b446299568 . _:b446299793 . _:b446299389 . _:b446299569 . _:b446299687 . _:b446299570 . _:b446299571 . _:b446299596 . _:b446299580 . _:b446299388 . _:b446299581 . _:b446299582 . _:b446299583 . _:b446299576 . _:b446299391 . _:b446299577 . _:b446299578 . . _:b446299579 . . _:b446299556 . _:b446299390 . _:b446299557 . _:b446299558 . _:b446299614 . _:b446299559 . _:b446299552 . _:b446299385 . _:b446299553 . _:b446299359 . _:b9111656 "results" . _:b446299554 . _:b446299555 . . _:b446299564 . _:b446299384 . _:b446299565 . _:b446299566 . _:b446299567 . . _:b446299404 . _:b446299560 . _:b446299391 . _:b446299387 . _:b446299561 . _:b446299562 . _:b446299563 . _:b446299604 . _:b446299386 . _:b446299605 . _:b446299606 . _:b446299607 . _:b446299600 . _:b446299601 . _:b446299602 . _:b446299603 . _:b446299675 . _:b446299612 . _:b446299613 . . _:b446299614 . _:b446299615 . _:b446299608 . _:b446299609 . _:b446299610 . _:b446299611 . _:b446299588 . _:b446299589 . _:b446299590 . . _:b446299591 . _:b446299584 . _:b446299585 . _:b446299586 . _:b446299767 . _:b446299587 . _:b446299596 . _:b446299597 . _:b446299598 . _:b446299599 . _:b446299592 . _:b446299913 . _:b446299593 . _:b446299594 . _:b446299595 . _:b446299636 . _:b446299637 . _:b446299638 . _:b446299794 . _:b446299639 . _:b446299632 . _:b446299633 . _:b446299634 . _:b446299635 . _:b446299644 . _:b446299645 . _:b446299701 . _:b446299646 . _:b446299647 . _:b446299640 . _:b446299641 . _:b446299642 . _:b446299643 . _:b446299985 . _:b446299620 . _:b446299621 . _:b446299622 . _:b446299623 . _:b446299616 . _:b446299617 . _:b446299618 . _:b446299619 . _:b446299628 . _:b446299629 . _:b446299630 . _:b446299631 . _:b446299624 . _:b446299625 . _:b446299626 . _:b446299627 . . _:b446299583 . _:b446299729 . . . . . _:b446299947 . . . . _:b446299705 . _:b446299635 . _:b9111657 "As AA and GBM patients differ in their prognoses,>>18<<,19 efficacy analyses were repeated on an exploratory basis separately for the 2 subpopulations of AA and GBM patients." . . _:b446299762 . . _:b9111663 . . _:b446299504 . . _:b446299554 . . _:b446299649 . _:b446299536 . . . _:b446299899 . _:b446299646 . _:b446299975 . _:b446299971 . . _:b446299693 . _:b446299611 . . . _:b446299891 . _:b446299358 . . . . _:b446299302 . . _:b446299466 . . . . _:b446299488 . _:b446299496 . _:b446299287 "11"^^ . _:b446299685 . _:b446299286 "11"^^ . _:b446299375 . . _:b446299307 . _:b446299285 "12"^^ . _:b446299505 . . _:b446299890 . _:b446299601 . . _:b446299550 . _:b446299586 . . _:b446299877 . _:b446299312 . _:b446299964 . _:b446299294 "9"^^ . . _:b446299295 "8"^^ . . _:b446299425 . _:b446299292 "9"^^ . _:b446299293 "9"^^ . . . _:b446299960 . _:b446299290 "9"^^ . _:b446299291 "9"^^ . _:b446299289 "10"^^ . _:b446299735 . . _:b446299288 "11"^^ . _:b446299302 "7"^^ . . _:b446299303 "7"^^ . _:b446299318 . _:b446299552 . _:b446299300 "7"^^ . . _:b446299301 "7"^^ . . _:b9111679 "The suppression of immune reactions is commonly observed in patients with high-grade glioma.>>27<< A major factor contributing to the suppression of the immune system is TGF-\u03B22, as it has multiple effects on immunoregulatory functions, including the inhibition of lymphokine-activated killer cells and T-lymphocyte development and" . _:b446299298 "8"^^ . _:b9111668 . _:b446299612 . . _:b446299299 "7"^^ . _:b446299778 . . _:b446299296 "8"^^ . . . . _:b446299297 "8"^^ . _:b446299310 "6"^^ . _:b446299311 "6"^^ . _:b446299723 . _:b446299402 . . . _:b446299308 "7"^^ . _:b446299309 "6"^^ . . _:b446299306 "7"^^ . _:b446299768 . . _:b446299316 . _:b446299307 "7"^^ . _:b446299902 . . _:b446299304 "7"^^ . _:b446299809 . _:b446299305 "7"^^ . _:b446299443 . _:b446299318 "6"^^ . _:b446299319 "6"^^ . . _:b446299316 "6"^^ . . _:b446299317 "6"^^ . _:b446299415 . _:b446299314 "6"^^ . _:b446299306 . _:b446299315 "6"^^ . _:b446299312 "6"^^ . . _:b446299313 "6"^^ . _:b446299422 . _:b446299325 "5"^^ . . _:b446299324 "5"^^ . _:b446299327 "5"^^ . . _:b446299326 "5"^^ . _:b446299321 "5"^^ . _:b446299320 "6"^^ . _:b446299323 "5"^^ . _:b446299322 "5"^^ . _:b446299333 "5"^^ . _:b446299332 "5"^^ . _:b9111670 "standard\u201D endpoint for oncology trials.21,22 However, it has turned out in recent years that this may not be appropriate for therapies that have a completely different mode of action from fast-acting cytotoxic or cytoreductive agents.>>22<<,23 This particularly applies to immuno-based therapies, such as trabedersen, which rely on building an immune response over time." . _:b446299860 . _:b446299335 "5"^^ . _:b446299619 . _:b446299740 . _:b446299334 "5"^^ . . _:b446299329 "5"^^ . _:b446299910 . _:b446299328 "5"^^ . . _:b446299331 "5"^^ . . _:b446299626 . _:b446299330 "5"^^ . . _:b446299341 "4"^^ . _:b446299405 . _:b446299340 "5"^^ . _:b446299671 . _:b446299839 . _:b446299343 "4"^^ . _:b446299659 . _:b446299342 "4"^^ . _:b446299473 . _:b446299337 "5"^^ . . _:b446299336 "5"^^ . _:b446299339 "5"^^ . _:b446299868 . . . . _:b446299338 "5"^^ . . . _:b446299349 "4"^^ . _:b446299362 . _:b446299882 . _:b446299730 . _:b446299348 "4"^^ . _:b446299351 "4"^^ . _:b446299350 "4"^^ . _:b446299345 "4"^^ . _:b446299696 . _:b446299344 "4"^^ . _:b446299662 . . _:b446299347 "4"^^ . _:b446299774 . _:b446299346 "4"^^ . _:b446299957 . _:b446299760 . _:b446299357 "4"^^ . . . _:b446299549 . _:b446299356 "4"^^ . _:b446299340 . _:b446299814 . . _:b446299661 . _:b446299359 "4"^^ . _:b446299358 "4"^^ . _:b446299568 . _:b446299353 "4"^^ . _:b446299352 "4"^^ . _:b446299424 . . _:b446299355 "4"^^ . _:b446299291 . _:b446299869 . _:b446299354 "4"^^ . . _:b446299365 "4"^^ . _:b446299364 "4"^^ . _:b446299956 . _:b446299367 "4"^^ . _:b446299366 "4"^^ . . _:b446299361 "4"^^ . _:b446299360 "4"^^ . _:b446299363 "4"^^ . .