nkhani

Cachexia ndi matenda a systemic omwe amadziwika ndi kuchepa thupi, minofu ndi adipose minofu atrophy, komanso kutupa kwadongosolo. Cachexia ndi imodzi mwazovuta zazikulu komanso zomwe zimayambitsa kufa kwa odwala khansa. Akuti chiwerengero cha cachexia mwa odwala khansa chikhoza kufika 25% mpaka 70%, ndipo pafupifupi anthu 9 miliyoni padziko lonse amadwala cachexia chaka chilichonse, 80% mwa iwo omwe akuyembekezeka kufa mkati mwa chaka chimodzi atazindikira matendawa. Kuphatikiza apo, cachexia imakhudza kwambiri moyo wa odwala (QOL) ndikuwonjezera poizoni wokhudzana ndi chithandizo.

Kuchita bwino kwa cachexia ndikofunikira kwambiri pakuwongolera moyo wabwino komanso kuwunika kwa odwala khansa. Komabe, ngakhale patsogolo pang'onopang'ono pa kafukufuku wa pathophysiological njira za cachexia, mankhwala ambiri opangidwa pogwiritsa ntchito njira zomwe zingatheke ndi ochepa chabe kapena osagwira ntchito. Pakali pano palibe chithandizo chogwira ntchito chovomerezeka ndi US Food and Drug Administration (FDA).

Cachexia (wasting syndrome) ndi yofala kwambiri kwa odwala omwe ali ndi mitundu yambiri ya khansa, yomwe nthawi zambiri imayambitsa kuwonda, kuwonda kwa minofu, kuchepa kwa moyo, kusokonezeka kwa ntchito, ndi kufupikitsa kupulumuka. Malingana ndi mfundo zomwe mayiko onse amavomereza, multifactorial syndrome iyi imatanthauzidwa ngati chiwerengero cha thupi (BMI, kulemera [kg] kugawidwa ndi kutalika [m] squared) zosakwana 20 kapena, kwa odwala omwe ali ndi sarcopenia, kuchepa kwa thupi kuposa 5% m'miyezi isanu ndi umodzi, kapena kuchepa kwa 2%. Pakalipano, palibe mankhwala omwe avomerezedwa ku United States ndi ku Ulaya makamaka pofuna kuchiza cachexia ya khansa, zomwe zimapangitsa kuti pakhale njira zochepa zothandizira.
Malangizo aposachedwa omwe amalimbikitsa olanzapine otsika kuti azitha kudya komanso kulemera kwa odwala omwe ali ndi khansa yapamwamba kwambiri amachokera ku zotsatira za kafukufuku wapakatikati. Kuphatikiza pa izi, kugwiritsa ntchito ma progesterone kwanthawi yayitali kapena glucocorticoids kungapereke zopindulitsa zochepa, koma pali chiopsezo cha zotsatira zoyipa (monga kugwiritsa ntchito progesterone komwe kumakhudzana ndi zochitika za thromboembolic). Mayesero achipatala a mankhwala ena alephera kusonyeza mphamvu zokwanira kuti apambane kuvomerezedwa ndi malamulo. Ngakhale kuti anamorine (mtundu wapakamwa wa kukula kwa hormone yotulutsa ma peptide) yavomerezedwa ku Japan kuti ichiritse cachexia ya khansa, mankhwalawa amangowonjezera maonekedwe a thupi mpaka kufika pamlingo winawake, sanasinthe mphamvu yogwira, ndipo pamapeto pake sanavomerezedwe ndi US Food and Drug Administration (FDA). Pakufunika mwachangu chithandizo chamankhwala chotetezeka, chothandiza komanso cholunjika cha cachexia ya khansa.
Growth differentiation factor 15 (GDF-15) ndi cytokine yomwe imayambitsa nkhawa yomwe imamangiriza ku glia-derived neurotrophic factor family receptor alpha-like protein (GFRAL) mu ubongo wapambuyo. Njira ya GDF-15-GFRAL yadziwika kuti ndiyomwe imayambitsa matenda a anorexia ndi kulemera kwa thupi, ndipo imagwira ntchito pa matenda a cachexia. Pazitsanzo za nyama, GDF-15 imatha kuyambitsa cachexia, ndipo kuletsa kwa GDF-15 kumatha kuchepetsa chizindikirochi. Kuonjezera apo, magulu okwera a GDF-15 mwa odwala khansa amagwirizanitsidwa ndi kuchepa kwa thupi ndi minofu ya chigoba, kuchepa kwa mphamvu, ndi kufupikitsa kupulumuka, kutsindika kufunika kwa GDF-15 monga chithandizo chotheka kuchiza.
ponsegromab (PF-06946860) ndi anti-monoclonal antibody yosankha kwambiri yomwe imatha kumangirira kuzungulira GDF-15, potero imalepheretsa kuyanjana kwake ndi cholandilira cha GFRAL. M'mayesero ang'onoang'ono otseguka a gawo la 1b, odwala 10 omwe ali ndi khansa ya cachexia ndi ma GDF-15 okwera kwambiri ozungulira anachitidwa ndi ponsegromab ndipo adawonetsa kusintha kwa kulemera, chilakolako, ndi kuchita masewera olimbitsa thupi, pamene ma seramu a GDF-15 anali oletsedwa ndipo zochitika zovuta zinali zochepa. Kutengera izi, tidachita mayeso achipatala a Phase 2 kuti tiwone chitetezo ndi mphamvu ya ponsegromab kwa odwala omwe ali ndi khansa ya cachexia yokhala ndi milingo yozungulira ya GDF-15, poyerekeza ndi placebo, kuyesa lingaliro lakuti GDF-15 ndiye matenda oyamba a matendawa.
Kafukufukuyu anaphatikizapo odwala achikulire omwe ali ndi cachexia yokhudzana ndi khansa (khansa ya m'mapapo yomwe si yaing'ono, khansara ya m'mapapo, kapena khansa ya m'mapapo) yokhala ndi seramu GDF-15 mlingo wa osachepera 1500 pg / ml, chiwerengero cha kulimbitsa thupi cha Eastern Tumor Consortium (ECOG) cha ≤3, ndi moyo wa miyezi yosachepera 4.
Odwala omwe adalembetsa adapatsidwa mwachisawawa kuti alandire Mlingo wa 3 wa ponsegromab 100 mg, 200 mg, kapena 400 mg, kapena placebo, mosadukiza masabata anayi aliwonse mu chiŵerengero cha 1: 1: 1. Chomaliza chachikulu chinali kusintha kwa kulemera kwa thupi poyerekeza ndi chiyambi pa masabata a 12. Mapeto ofunikira achiwiri anali kusintha kuchokera pa chiyambi cha anorexia cachexia Sub-Scale (FAACT-ACS), kuwunika kwa ntchito yochizira ya anorexia cachexia. Mapeto ena achiwiri adaphatikizapo kuchuluka kwa zizindikiro za cachexia zokhudzana ndi khansa, kusintha koyambira pakuchita masewera olimbitsa thupi komanso kupita komwe kumayesedwa pogwiritsa ntchito zida zathanzi zama digito. Zofunikira zochepa za nthawi yovala zimatchulidwiratu. Kuwunika kwachitetezo kumaphatikizapo kuchuluka kwa zochitika zoyipa panthawi ya chithandizo, zotsatira za mayeso a labotale, zizindikiro zofunika, ndi electrocardiograms. Mapeto ofufuza adaphatikizapo kusintha koyambira mu lumbar skeletal muscle index (chigoba cha minofu chogawidwa ndi kutalika kwa squared) chogwirizana ndi systemic skeletal muscle.

Odwala okwana 187 adapatsidwa mwayi wolandila ponsegromab 100 mg (odwala 46), 200 mg (odwala 46), 400 mg (odwala 50), kapena placebo (odwala 45). Makumi asanu ndi awiri mphambu anayi (40 peresenti) anali ndi khansa ya m'mapapo yosakhala yaing'ono, 59 (32 peresenti) anali ndi khansa ya m'mapapo, ndipo 54 (29 peresenti) anali ndi khansa ya colorectal.
Kusiyana pakati pa magulu a 100 mg, 200 mg, ndi 400 mg ndi placebo anali 1.22 kg, 1.92 kg, ndi 2.81 kg, motsatana.

Chiwerengerochi chikuwonetsa mapeto oyambirira (kusintha kwa kulemera kwa thupi kuchokera pa chiyambi mpaka masabata a 12) kwa odwala khansa ya cachexia m'magulu a ponsegromab ndi placebo. Pambuyo pokonzekera chiopsezo cha imfa ndi zochitika zina zofanana, monga kusokonezeka kwa chithandizo, mapeto oyambirira adawunikidwa ndi chitsanzo cha Emax cha stratified pogwiritsa ntchito zotsatira za sabata 12 kuchokera ku Bayesian joint longitudinal analysis (kumanzere). Mapeto oyambirira adawunikidwanso mofananamo, pogwiritsa ntchito mipherezero yomwe ikuyembekezeredwa pa chithandizo chenichenicho, pamene zowonera pambuyo pa zochitika zonse zomwe zinachitikira zinachepetsedwa (chithunzi choyenera). Nthawi zachidaliro (zosonyezedwa m'nkhani

Zotsatira za 400 mg ponsegromab pa kulemera kwa thupi zinali zogwirizana m'magulu akuluakulu omwe adakhazikitsidwa kale, kuphatikizapo mtundu wa khansa, serum GDF-15 level quartile, platinum-based chemotherapy exposure, BMI, ndi kutupa kwapachiyambi. Kusintha kwa kulemera kunali kogwirizana ndi GDF-15 inhibition pa masabata a 12.

Kusankhidwa kwamagulu ang'onoang'ono ofunikira kunachokera ku kafukufuku wapambuyo-hoc wa Bayesian longitudinal longitudinal, womwe unachitika pambuyo pa kusintha kwa ngozi ya mpikisano wa imfa potengera zomwe zikuyembekezeredwa za njira ya chithandizo. Nthawi zachidaliro siziyenera kugwiritsidwa ntchito m'malo mwa kuyesa kwamalingaliro popanda kusintha kangapo. BMI imayimira index mass index, CRP imayimira C-reactive protein, ndipo GDF-15 imayimira kukula kwa 15 factor.
Pachiyambi, chiwerengero chachikulu cha odwala ponsegromab 200 mg gulu adanena kuti palibe kuchepa kwa njala; Poyerekeza ndi placebo, odwala a ponsegromab 100 mg ndi 400 mg magulu adanenanso za kusintha kwa njala kuyambira pachiyambi pa masabata 12, ndi kuwonjezeka kwa FAACT-ACS scores 4.12 ndi 4.5077, motero. Panalibe kusiyana kwakukulu muzochitika za FAACT-ACS pakati pa gulu la 200 mg ndi gulu la placebo.
Chifukwa cha zofunikira za nthawi yovala zomwe zidatchulidwa kale ndi zovuta za chipangizo, odwala 59 ndi 68, motsatana, adapereka deta yokhudzana ndi kusintha kwa zochitika zolimbitsa thupi komanso zomaliza zomwe zimagwirizana ndi zoyambira. Pakati pa odwalawa, poyerekeza ndi gulu la placebo, odwala mu gulu la 400 mg anali ndi kuwonjezeka kwa ntchito yonse pa masabata a 12, ndi kuwonjezeka kwa maminiti a 72 osachita masewera olimbitsa thupi tsiku lililonse. Kuonjezera apo, gulu la 400 mg linalinso ndi kuwonjezeka kwa lumbar skeletal muscle index pa sabata 12.
Zochitika zoyipa zinali 70% mu gulu la ponsegromab, poyerekeza ndi 80% mu gulu la placebo, ndipo zidachitika mu 90% ya odwala omwe amalandila chithandizo chamankhwala choletsa khansa panthawi imodzi. Kuchuluka kwa nseru ndi kusanza kunali kochepa mu gulu la ponsegromab.