I-Cachexia yisifo se-systemic esibonakala ngokuncipha kwesisindo, i-muscle ne-adipose tissue atrophy, nokuvuvukala kwesistimu. I-Cachexia ingenye yezinkinga ezinkulu nezimbangela zokufa kweziguli ezinomdlavuza. Kulinganiselwa ukuthi izigameko ze-cachexia ezigulini ezinomdlavuza zingafinyelela ku-25% kuya ku-70%, futhi cishe abantu abayizigidi ezingu-9 emhlabeni wonke bahlushwa yi-cachexia unyaka ngamunye, u-80% wabo okulindeleke ukuthi bafe ungakapheli unyaka owodwa bexilongwa. Ngaphezu kwalokho, i-cachexia ithinta kakhulu izinga lempilo yesiguli (QOL) futhi ibhebhethekisa ubuthi obuhlobene nokwelashwa.
Ukungenelela okuphumelelayo kwe-cachexia kubaluleke kakhulu ekuthuthukiseni izinga lempilo kanye nokubikezelwa kweziguli ezinomdlavuza. Kodwa-ke, naphezu kwenqubekelaphambili ethile ocwaningweni lwezinqubo ze-pathophysiological of cachexia, izidakamizwa eziningi ezakhiwe ngokusekelwe ezindleleni ezingase zibe khona zisebenza kancane noma azisebenzi. Okwamanje akukho ukwelashwa okusebenzayo okugunyazwe i-US Food and Drug Administration (FDA).
I-Cachexia (i-wasting syndrome) ivame kakhulu ezigulini ezinezinhlobo eziningi zomdlavuza, ngokuvamile okuholela ekwehleni kwesisindo, ukuwohloka kwemisipha, izinga lokuphila elincishisiwe, ukungasebenzi kahle, kanye nokusinda okufushane. Ngokwezindinganiso okuvunyelwene ngazo emhlabeni wonke, lesi sifo sichazwa ngokuthi inkomba yesisindo somzimba (BMI, isisindo [kg] ehlukaniswa ngobude [m] isikwele) esingaphansi kuka-20 noma, ezigulini ezine-sarcopenia, ukwehla kwesisindo esingaphezu kuka-5% ezinyangeni eziyisithupha, noma ukwehla kwesisindo esingaphezu kuka-2%. Njengamanje, azikho izidakamizwa ezivunyelwe e-United States naseYurophu ngokukhethekile ukwelapha i-cachexia yomdlavuza, okuholela ezindlekweni zokwelashwa ezilinganiselwe.
Imihlahlandlela yakamuva encoma umthamo ophansi we-olanzapine ukuze kuthuthukiswe isifiso sokudla nesisindo ezigulini ezinomdlavuza othuthukisiwe ngokuyinhloko isekelwe emiphumeleni yocwaningo lwesikhungo esisodwa. Ngaphezu kwalokhu, ukusetshenziswa kwesikhashana kwe-progesterone analogue noma i-glucocorticoid kungase kunikeze izinzuzo ezilinganiselwe, kodwa kunengozi yemiphumela emibi (njengokusebenzisa i-progesterone ehambisana nezenzakalo ze-thromboembolic). Izivivinyo zomtholampilo zeminye imithi yehlulekile ukukhombisa ukusebenza kahle ngokwanele ukuze kutholakale imvume yokulawula. Nakuba i-anamorine (inguqulo yomlomo ye-hormone yokukhula ekhulula ama-peptide) ivunyelwe eJapane ukwelashwa kwe-cachexia yomdlavuza, lesi sidakamizwa sandisa ukwakheka komzimba ngezinga elithile, asizange sithuthukise amandla okubamba, futhi ekugcineni asivunyelwe yi-US Food and Drug Administration (FDA). Kunesidingo esiphuthumayo sokwelashwa okuphephile, okusebenzayo nokuhlosiwe kwe-cachexia yomdlavuza.
I-Growth differentiation factor 15 (GDF-15) i-cytokine ebangelwa ukucindezeleka ebophezela ku-glia-derived neurotrophic factor family receptor alpha-like protein (GFRAL) ebuchosheni obungemuva. Indlela ye-GDF-15-GFRAL ikhonjwe njengesilawuli esikhulu se-anorexia nokulawulwa kwesisindo, futhi idlala indima ku-pathogenesis ye-cachexia. Kumamodeli ezilwane, i-GDF-15 ingenza i-cachexia, futhi ukuvinjelwa kwe-GDF-15 kungadambisa lolu phawu. Ukwengeza, amazinga aphakeme e-GDF-15 ezigulini ezinomdlavuza ahlotshaniswa nokuncipha kwesisindo somzimba kanye nesisindo somzimba wamathambo, amandla anciphile, nokusinda okufushane, okugcizelela ukubaluleka kwe-GDF-15 njengendlela yokwelapha engaba khona.
I-ponsegromab (PF-06946860) iyi-antibody monoclonal ekhethiwe kakhulu ekwazi ukubophezela ekujikelezeni kwe-GDF-15, ngaleyo ndlela ivimbele ukusebenzisana kwayo nesamukeli se-GFRAL. Esivivinyweni esincane esivulekile sesigaba se-1b, iziguli ezingu-10 ezinomdlavuza we-cachexia kanye namazinga aphezulu ajikelezayo e-GDF-15 zaphathwa nge-ponsegromab futhi zabonisa ukuthuthukiswa kwesisindo, isifiso sokudla, nokusebenza komzimba, kuyilapho amazinga e-serum GDF-15 ayevinjelwe futhi izenzakalo ezimbi zaziphansi. Ngokusekelwe kulokhu, senze uhlolo lomtholampilo lweSigaba 2 ukuze sihlole ukuphepha nokusebenza ngempumelelo kwe-ponsegromab ezigulini ezinomdlavuza we-cachexia ezinamazinga ajikelezayo e-GDF-15, uma kuqhathaniswa ne-placebo, ukuhlola umbono wokuthi i-GDF-15 iyi-pathogenesis eyinhloko yesifo.
Ucwaningo lwaluhlanganisa iziguli ezikhulile ezine-cachexia ezihlotshaniswa nomdlavuza (umdlavuza wamaphaphu ongewona omncane, umdlavuza we-pancreatic, noma umdlavuza we-colorectal) enezinga le-serum GDF-15 okungenani elingu-1500 pg/ml, i-Eastern Tumor Consortium (ECOG) isikolo sokufaneleka esingu-≤3, neminyaka yokuphila okungenani izinyanga ezi-4.
Iziguli ezibhalisiwe zabelwa ngokungahleliwe ukuthola imithamo emi-3 ye-ponsegromab 100 mg, 200 mg, noma 400 mg, noma i-placebo, ngaphansi kwesikhumba njalo emavikini angu-4 ngokwesilinganiso esingu-1:1:1. Isiphetho esiyinhloko kwaba ukushintsha kwesisindo somzimba ngokuhlobene nesisekelo emavikini angu-12. Isiphetho sesibili esiyisihluthulelo kwaba ukuguqulwa kusukela kusisekelo kumphumela we-anorexia cachexia Sub-Scale (FAACT-ACS), ukuhlolwa komsebenzi wokwelapha we-anorexia cachexia. Ezinye iziphetho zesibili zazihlanganisa izikolo zedayari yezimpawu ze-cachexia ezihambisana nomdlavuza, izinguquko eziyisisekelo emsebenzini womzimba kanye namaphoyinti okuphila okukalwa kusetshenziswa amadivaysi ezempilo edijithali agqokekayo. Izidingo zesikhathi esincane sokugqoka zicaciswa kusengaphambili. Ukuhlolwa kokuphepha kwakuhlanganisa inani lezehlakalo ezimbi phakathi nokwelashwa, imiphumela yokuhlolwa kwaselabhorethri, izimpawu ezibalulekile, nama-electrocardiograms. Iziphetho zokuhlola zazihlanganisa izinguquko eziyisisekelo ku-lumbar skeletal muscle index (indawo ye-skeletal muscle ehlukaniswe ngobude obuyisikwele) ehambisana ne-systemic skeletal muscle.
Isamba seziguli eziyi-187 zabelwa ngokungahleliwe ukuthola i-ponsegromab 100 mg (iziguli ezingama-46), 200 mg (iziguli ezingama-46), 400 mg (iziguli ezingama-50), noma i-placebo (iziguli ezingama-45). Amashumi ayisikhombisa nane (amaphesenti angu-40) anomdlavuza wamaphaphu ongewona omncane, ama-59 (amaphesenti angu-32) anomdlavuza we-pancreatic, kanti ama-54 (amaphesenti angu-29) anomdlavuza we-colorectal.
Umehluko phakathi kwamaqembu we-100 mg, 200 mg, no-400 mg kanye ne-placebo wawungu-1.22 kg, 1.92 kg, no-2.81 kg, ngokulandelana.
Isibalo sibonisa isiphetho esiyinhloko (ukushintsha kwesisindo somzimba kusuka kwesisekelo kuya emavikini angu-12) ezigulini ezinomdlavuza we-cachexia ku-ponsegromab namaqembu e-placebo. Ngemva kokulungiswa kwengozi eqhudelanayo yokufa nezinye izenzakalo ezihambisanayo, ezifana nokuphazamiseka kokwelashwa, isiphetho esiyinhloko sahlaziywa imodeli ye-Emax ene-stratified kusetshenziswa imiphumela yeviki le-12 kusukela ekuhlaziyweni okuhlangene kwe-Bayesian longitudinal (kwesokunxele). Iziphetho eziyinhloko nazo zahlaziywa ngendlela efanayo, kusetshenziswa okuhlosiwe okulinganiselwe kokwelashwa kwangempela, lapho ukubhekwa ngemva kwazo zonke izenzakalo ezihambisanayo kwancishiswa (isibalo esilungile). Izikhawu zokuzethemba (ezikhonjiswe esihlokweni
Umphumela we-400 mg ponsegromab esisindweni somzimba wawungaguquguquki kuwo wonke amaqeqebana amakhulu asethiwe ngaphambilini, okuhlanganisa uhlobo lomdlavuza, i-serum GDF-15 level quartile, ukuchayeka ku-chemotherapy okusekelwe ku-platinum, i-BMI, kanye nokuvuvukala okuyisisekelo kwesistimu. Ukushintsha kwesisindo kwakuhambisana nokuvinjelwa kwe-GDF-15 emavikini angu-12.
Ukukhethwa kwama-subgroups abalulekile kwakusekelwe ekuhlaziyweni kwe-Bayesian longitudinal yangemuva kwe-hoc, okwenziwa ngemva kokulungiswa kwengozi yokuncintisana yokufa ngokusekelwe ekuhlosweni okulinganiselwe kwesu lokwelapha. Izikhawu zokuzethemba akufanele zisetshenziswe esikhundleni sokuhlolwa kwe-hypothesis ngaphandle kokulungiswa okuningi. I-BMI imele inkomba yesisindo somzimba, i-CRP imele amaprotheni e-C-reactive, kanti i-GDF-15 imele isici esihlukanisa ukukhula esingu-15.
Ekuqaleni, ingxenye ephezulu yeziguli eqenjini le-ponsegromab 200 mg ibike ukuthi akukho kuncipha kwesifiso sokudla; Uma kuqhathaniswa ne-placebo, iziguli eziseqenjini le-ponsegromab 100 mg kanye ne-400 mg zibike ukuthuthuka kwesifiso sokudla kusukela ekuqaleni emavikini angu-12, nokwanda kwamaphuzu e-FAACT-ACS angu-4.12 no-4.5077, ngokulandelana. Kwakungekho mehluko obalulekile kuzikolo ze-FAACT-ACS phakathi kweqembu le-200 mg neqembu le-placebo.
Ngenxa yezidingo zesikhathi sokugqoka ezishiwo ngaphambili kanye nezinkinga zedivayisi, iziguli ezingama-59 nezingu-68, ngokulandelana kwazo, zinikeze idatha ngezinguquko zomsebenzi womzimba kanye namaphoyinti okuphila okuhambisana nesisekelo. Phakathi kwalezi ziguli, uma kuqhathaniswa neqembu le-placebo, iziguli eziseqenjini le-400 mg ziye zanda emsebenzini jikelele emavikini angu-12, ngokunyuka kwemizuzu ye-72 yokungahlali phansi komzimba ngosuku. Ngaphezu kwalokho, iqembu le-400 mg liphinde libe nokwanda kwe-lumbar skeletal muscle index ngeviki le-12.
Izehlakalo zezehlakalo ezimbi zingama-70% eqenjini le-ponsegromab, uma kuqhathaniswa nama-80% eqenjini le-placebo, futhi zenzeke ku-90% weziguli ezithola ukwelashwa kwe-systemic anticancer kanyekanye. Izehlakalo zokucanuzela kwenhliziyo nokuhlanza zaziphansi eqenjini le-ponsegromab.
Isikhathi sokuthumela: Oct-05-2024