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I-Cachexia sisifo se-systemic esibonakaliswa ukunciphisa umzimba, i-muscle kunye ne-adipose tissue atrophy, kunye nokuvuvukala kwenkqubo. I-Cachexia yenye yeengxaki eziphambili kunye nezizathu zokufa kwizigulane ezinomhlaza. Kuqikelelwa ukuba iziganeko ze-cachexia kwizigulane ezinomhlaza zingafikelela kwi-25% ukuya kwi-70%, kwaye malunga ne-9 yezigidi zabantu kwihlabathi jikelele bahlushwa yi-cachexia ngonyaka, i-80% yabo kulindeleke ukuba bafe kunyaka omnye wokuxilongwa. Ukongezelela, i-cachexia ichaphazela kakhulu umgangatho wobomi besigulane (QOL) kwaye yandisa ubuthi obunxulumene nonyango.

Ungenelelo olusebenzayo lwe-cachexia lubaluleke kakhulu ekuphuculeni umgangatho wobomi kunye ne-prognosis yabaguli abanomhlaza. Nangona kunjalo, ngaphandle kwenkqubela phambili kuphononongo lweendlela ze-pathophysiological ye-cachexia, uninzi lwamachiza aphuhlisiwe ngokusekelwe kwiindlela ezinokwenzeka zisebenza ngokuyinxenye okanye zingasebenzi. Okwangoku alukho unyango olusebenzayo oluvunywe yi-US Food and Drug Administration (FDA).

I-Cachexia (i-wasting syndrome) ixhaphake kakhulu kwizigulane ezineentlobo ezininzi zomhlaza, ezihlala zikhokelela ekunciphiseni ubunzima, ukuchithwa kwemisipha, ukunciphisa umgangatho wobomi, ukungasebenzi kakuhle, kunye nokunciphisa ubomi. Ngokwemigangatho ekuvunyelwene ngayo ngamazwe ngamazwe, le syndrome ye-multifactorial ichazwa njengesalathisi sobunzima bomzimba (i-BMI, ubunzima [kg] ehlulwe ngobude [m] isikwere) esingaphantsi kwe-20 okanye, kwizigulane ezine-sarcopenia, ukulahlekelwa kwesisindo esingaphezu kwe-5% kwiinyanga ezintandathu, okanye ukulahlekelwa kwesisindo esingaphezu kwe-2%. Okwangoku, akukho machiza amkelweyo e-United States naseYurophu ngokukodwa kunyango lwe-cachexia yomhlaza, okukhokelela ekukhetheni okulinganiselweyo zonyango.
Izikhokelo zamva nje zincoma i-olanzapine ephantsi yokuphucula ukutya kunye nobunzima kwizigulane ezinomhlaza ophezulu kakhulu zisekelwe kwiziphumo zophando lweziko elinye. Ukongeza koku, ukusetyenziswa kwexesha elifutshane le-progesterone analogues okanye i-glucocorticoids kunokubonelela ngeenzuzo ezilinganiselweyo, kodwa kukho umngcipheko wemiphumo emibi (efana nokusetyenziswa kweprogesterone ehambelana neziganeko ze-thromboembolic). Ulingo lwezonyango lwamanye amachiza aluphumelelanga ukubonisa ukusebenza ngokwaneleyo ukuze kuphunyezwe imvume yolawulo. Nangona i-anamorine (inguqulelo yomlomo ye-hormone yokukhula ekhupha i-peptides) ivunyiwe eJapan kunyango lwe-cachexia yomhlaza, iyeza lonyusa kuphela ukubunjwa komzimba kwinqanaba elithile, alizange liphucule amandla okubamba, kwaye ekugqibeleni alivunywanga yi-US Food and Drug Administration (FDA). Kukho imfuneko engxamisekileyo yonyango olukhuselekileyo, olusebenzayo nolujoliswe kuyo lwecachexia yomhlaza.
I-Growth differentiation factor 15 (GDF-15) yi-cytokine ebangela uxinzelelo oludibanisa ne-glia-derived neurotrophic factor family receptor alpha-like protein (GFRAL) kwingqondo yangasemva. Indlela ye-GDF-15-GFRAL ichongiwe njengomlawuli omkhulu we-anorexia kunye nokulawulwa kobunzima, kwaye idlala indima kwi-pathogenesis ye-cachexia. Kwiimodeli zezilwanyana, i-GDF-15 inokubangela i-cachexia, kwaye inhibition ye-GDF-15 inokunciphisa le mpawu. Ukongezelela, amanqanaba aphakamileyo e-GDF-15 kwizigulane zomhlaza adibaniswa nokunciphisa ubunzima bomzimba kunye nobunzima be-skeletal muscle, ukunciphisa amandla, kunye nokusinda okufutshane, ukugxininisa ixabiso le-GDF-15 njengento ekujoliswe kuyo yonyango.
i-ponsegromab (PF-06946860) yi-antibody ye-monoclonal ekhethiweyo kakhulu ekwazi ukubophelela ukujikeleza i-GDF-15, ngaloo ndlela inqanda ukusebenzisana kwayo ne-GFRAL receptor. Kwinqanaba elincinci le-label-label ye-1b yolingo, izigulane ze-10 ezinomdlavuza we-cachexia kunye nokuphakama okujikelezayo kwe-GDF-15 amanqanaba aphathwa nge-ponsegromab kwaye abonise ukuphuculwa kwesisindo, ukutya, kunye nomsebenzi womzimba, ngelixa i-serum GDF-15 yayinqatshelwe kwaye iziganeko ezimbi ziphantsi. Ngokusekelwe kule nto, senze uvavanyo lwekliniki lweSigaba se-2 ukuvavanya ukhuseleko kunye nokusebenza kakuhle kwe-ponsegromab kwizigulane ezinomhlaza we-cachexia kunye namazinga aphakamileyo ajikelezayo e-GDF-15, xa kuthelekiswa ne-placebo, ukuvavanya i-hypothesis yokuba i-GDF-15 yi-pathogenesis ephambili yesifo.
Uphononongo lubandakanya izigulane zabantu abadala abane-cachexia ehambelana nomhlaza (umhlaza we-cell lung ongeyena omncinci, umhlaza we-pancreatic, okanye umhlaza we-colorectal) kunye ne-serum ye-GDF-15 inqanaba ubuncinane le-1500 pg / ml, i-Eastern Tumor Consortium (ECOG) inqanaba lokufaneleka kwe-≤3, kunye nexesha lokuphila ubuncinane kwiinyanga ze-4.
Izigulane ezibhalisiweyo zabelwa ngokungenamkhethe ukuba zifumane iidosi ze-3 ze-ponsegromab 100 mg, i-200 mg, okanye i-400 mg, okanye i-placebo, i-subcutaneously zonke iiveki ze-4 kwisilinganiselo se-1: 1: 1. Isiphelo sokuqala sasiyinguqu kwisisindo somzimba ngokubhekiselele kwisiseko kwiiveki ze-12. Isiphelo esiphambili sesibini sasiyinguqu ukusuka kwisiseko kwi-anorexia cachexia Sub-Scale (FAACT-ACS) amanqaku, uvavanyo lomsebenzi wonyango we-anorexia cachexia. Ezinye iziphelo zesibini ziquka i-cachexia ehambelana nomhlaza amanqaku edayari yeempawu, utshintsho olusisiseko kumsebenzi womzimba kunye neendawo zokuphela kwe-gait ezilinganiswe kusetyenziswa izixhobo zempilo ezinxitywayo zedijithali. Ubuncinci beemfuno zexesha lokunxiba zichazwe kwangaphambili. Uvavanyo lokhuseleko lubandakanya inani leziganeko ezimbi ngexesha lonyango, iziphumo zovavanyo lwebhubhoratri, iimpawu ezibalulekileyo, kunye ne-electrocardiograms. Iziphelo zokuhlola zibandakanya utshintsho olusisiseko kwisalathisi se-lumbar skeletal muscle (indawo ye-skeletal muscle eyahlulwe ngobude obuphindwe kabini) ehambelana ne-systemic skeletal muscle.

I-totali yezigulane ze-187 zabelwe ngokungenamkhethe ukufumana i-ponsegromab 100 mg (izigulane ze-46), i-200 mg (izigulane ze-46), i-400 mg (izigulane ze-50), okanye i-placebo (izigulane ze-45). Abangamashumi asixhenxe anesine (40 ekhulwini) babenomhlaza wemiphunga ongeyonxalenye encinci, i-59 (i-32 ekhulwini) inomhlaza we-pancreatic, kwaye i-54 (i-29 pesenti) inomhlaza we-colorectal.
Umahluko phakathi kwe-100 mg, i-200 mg, kunye ne-400 mg amaqela kunye ne-placebo yayiyi-1.22 kg, i-1.92 kg, kunye ne-2.81 kg, ngokulandelanayo.

Umzobo ubonisa isiphelo sokuqala (utshintsho kwisisindo somzimba ukusuka kwisiseko ukuya kwiiveki ze-12) kwizigulane ezinomdlavuza we-cachexia kwi-ponsegromab kunye namaqela e-placebo. Emva kokulungelelaniswa komngcipheko okhuphisanayo wokufa kunye nezinye iziganeko ezihambelanayo, ezifana nokuphazamiseka kwonyango, isiphelo esiphambili sahlalutya imodeli ye-Emax ene-stratified usebenzisa iziphumo zeveki ye-12 ukusuka kwi-Bayesian joint longitudinal analysis (ngasekhohlo). Iziphelo eziphambili nazo zahlalutywa ngendlela efanayo, kusetyenziswa iithagethi eziqikelelwayo zonyango lwangempela, apho ukuqwalaselwa emva kwazo zonke iziganeko ezihambelanayo zancitshiswa (umzobo ochanekileyo). Amaxesha okuzithemba (aboniswe kwinqaku

Impembelelo ye-400 mg ponsegromab kubunzima bomzimba yayingaguquguquki kuwo onke amacandelwana asele esetyenzisiwe, kubandakanywa uhlobo lomhlaza, i-serum GDF-15 level quartile, exposure chemotherapy-based exposure chemotherapy, BMI, kunye nesiseko sokuvuvukala kwenkqubo. Utshintsho lobunzima lwaluhambelana ne-GDF-15 inhibition kwiiveki ze-12.

Ukukhethwa kwamacandelwana abalulekileyo kwakusekelwe kwi-post-hoc ye-Bayesian yohlalutyo longitudinal longitudinal, olwenziwa emva kokulungelelaniswa komngcipheko wokukhuphisana wokufa ngokusekelwe ekujoliswe kuyo kuqikelelo lwesicwangciso sonyango. Amaxesha okuzithemba akufuneki asetyenziswe endaweni yovavanyo lwe-hypothesis ngaphandle kohlengahlengiso oluninzi. I-BMI imele i-index mass body, i-CRP imele i-protein ye-C-reactive, kunye ne-GDF-15 imele ukwahlukana kokukhula kwe-15.
Kwisiseko, inani eliphezulu lezigulane kwi-ponsegromab ye-200 mg iqela libike ukuba akukho kuncipha kwesidlo; Xa kuthelekiswa ne-placebo, izigulane kwi-ponsegromab i-100 mg kunye ne-400 mg amaqela achaza ukuphuculwa kwesidlo ukusuka kwisiseko kwiiveki ze-12, kunye nokunyuka kwamanqaku e-FAACT-ACS ye-4.12 kunye ne-4.5077, ngokulandelanayo. Kwakungekho mmahluko obalulekileyo kumanqaku e-FAACT-ACS phakathi kweqela le-200 mg kunye neqela le-placebo.
Ngenxa yeemfuno zexesha lokunxiba ezichazwe kwangaphambili kunye nemiba yesixhobo, i-59 kunye ne-68 izigulane, ngokulandelanayo, zibonelele ngedatha malunga nokutshintsha komsebenzi womzimba kunye nokuphela kokuhamba ngokumalunga nesiseko. Phakathi kwezi zi gulane, xa kuthelekiswa neqela le-placebo, izigulane kwiqela le-400 mg ziye zanda kumsebenzi opheleleyo kwiiveki ze-12, kunye nokunyuka kwemizuzu ye-72 yokuzivocavoca umzimba ongekho phantsi ngosuku. Ukongezelela, iqela le-400 mg libuye libe nokunyuka kwesalathisi se-lumbar skeletal muscle ngeveki ye-12.
Iziganeko zeziganeko ezimbi zaziyi-70% kwiqela le-ponsegromab, xa kuthelekiswa ne-80% kwiqela le-placebo, kwaye zenzeke kwi-90% yezigulane ezifumana unyango lwe-anticancer lwe-systemic ngaxeshanye. Izehlo zesicaphucaphu kunye nokuhlanza zazisezantsi kwiqela le-ponsegromab.