Cancerananan ƙananan ƙwayar cutar huhu da ƙwaƙwalwar ƙwaƙwalwa
A baya can, ƙananan ciwon huhu na huhu (NSCLC) ƙwayoyin kwakwalwa suna da mummunan tsinkaye, tare da tsaka-tsakin lokacin rayuwa na watanni 7. Amma ƙayyadaddun maye gurbi sun haifar da ɗimbin jiyya da aka yi niyya don waɗannan ƙwayoyin cuta na kwakwalwa kuma suna iya haɓaka lokacin rayuwa gabaɗaya. Ana iya ganin sake fasalin ALK a cikin kusan kashi 2-7% na NSCLC, don haka ya zama makasudin warkewa don ci gaban NSCLC. Kwanan nan farfesa Zhang Isabella da Lu Bo daga Amurka sun buga wani sharhi mai alaka a cikin The Lancetonology, wanda yanzu an gabatar da shi kamar haka:.
Crizotinib is the first approved anti-ALK tyrosine kinase inhibitor after showing excellent comprehensive effects, but this effect has not been translated into the control of intracranial lesions. The central nervous system (CNS) is a common site of involvement in disease progression. Up to 60% of patients will experience metastasis at this site during treatment with crizotinib: this is due to poor intracranial penetration of the drug and the inherent resistance of the tumo inji.
Masu hanawa na ALK na ƙarni na biyu suna da kyakkyawar kulawa da raunin intracranial, amma basu dace ba, wanda ke buƙatar mu bincika wasu zaɓuɓɓukan magani. Wannan labarin shine bita game da rawar ALK a cikin metastasis na CNS, ALK da aka yi niyya don maganin raunin intracranial, da juriya ga jiyya na yanzu.
Matsayin shingen kwakwalwa-jini
Hannun kwakwalwar jini yana kare kwakwalwa daga shigarwar abubuwa masu guba, amma kuma yana sanya wuya ga magungunan tsarin ya isa kwakwalwa parenchyma. Daga mahangar toshewa, shingen kwakwalwa-kwakwalwa yana da halaye da yawa: alal misali, ci gaba da haɗuwa tsakanin ƙwayoyin endothelial da hadadden tsarin tallafi gami da pericytes da astrocytes na iya daidaita shingen kwakwalwar jini ta hanyar Paracrine Permeability; babban juriya, kusan sau 100 na naɓaɓɓun sassan jiki, tare da zaɓin toshe wasu ƙwayoyin polar.
Wani ɓangare na tsarin jiyya wanda ke ƙetare shingen ƙwaƙwalwar ƙwaƙwalwar jini ana fitar da shi daga masu jigilar ruwa. Mafi yawan masu jigilar kayan masarufi sune P-glycoprotein, sunadarai masu juriya na multidrug 1-6, ABCG2.
A cikin yanayin metastasis, mutuncin shingen kwakwalwar jini yana lalacewa. A wannan lokacin, tsarin jijiyoyin jini yana da kama da tsarin jijiyoyin jini na nama mai tasowa, kuma madaidaicin matsewar da ya lalace ya bayyana a matsayin vasculature mai iya jurewa. Dabaru don haɓaka haɓakar shingen jini-kwakwalwa sun haɗa da lalata shinge ta jiki ta hanyar radiotherapy, magungunan hypertonic, duban dan tayi mai ƙarfi, da analogs bradykinin.
Ƙarin shirye-shiryen da aka yi niyya da ke da alaƙa da masu hana ALK na iya hana miyagun ƙwayoyi daga fitar da su da kuma jigilar shi yadda ya kamata zuwa kwakwalwar kwakwalwa da ƙwayoyin tumo.
ALK sake shiryawa
Ana iya samun canje-canje masu nasaba da kwayar ALK a kusan 2-7% na NSCLC, mafi yawanci shine sauyawar EML4-ALK. Sake sakewa yana haifar da autophosphorylation da ci gaba da kunnawa na ALK, don haka kunna RAS da PI3K alamar sigina (duba saiti). Amfani da RAS na iya haifar da halaye masu ƙari na ƙari da kuma rashin lafiyar asibiti.
ALK rearrangement of cututtukan daji na kansa marasa kansar targeted therapy mechanism. It can directly target ALK rearrangement proteins (such as LDK378, X396, CH5424802); in addition, it can target upstream effectors (such as EGFR), or downstream pathways (such as PLC, JAK-STAT, KRAS-MEK-ERK, AKT-mTOR- Aurora A kinase) to inhibit cell cycle progression, survival, proliferation, and vascularization; it can target DNA repair; it can also target protein formation that stimulates cell growth (eg, EGFR ligands, VEGF).
Hakazalika da marasa lafiya tare da maye gurbi na EGFR, marasa lafiya tare da sake fasalin ALK na iya zama ƙanana, shan taba ƙasa ko shan taba fiye da marasa lafiya na daji, kuma kusan duka nau'in NSCLC ne na adenocarcinoma.
Yawancin karatu sun kimanta mahimmancin hangen nesa na sake gyara ALK a cikin NSCLC, amma sakamakon ya cakuɗe. Nazarin ya nuna cewa ALK ya sake fasalta NSCLC ya ninka haɗarin ci gaban cuta ko sake dawowa a cikin shekaru 5, kuma yana inganta ƙididdiga masu yawa. Marasa lafiya tare da sake fasalin ALK suna da ƙarin metastases lokacin da aka gano su, kuma haɗarin metastasis zuwa ga pericardium, pleura, da hanta ya fi girma. Har ila yau, akwai karatun da ke da'awar cewa sake fasalin ALK da marasa lafiya iri-iri sun yi kama da juna dangane da sake dawowa, rashin cutar cuta, da rayuwa gabaɗaya; akwai kuma karatun da ke nuna cewa sake fasalin ALK yana inganta rayuwa gaba ɗaya a cikin marasa lafiya I-III NSCLC.
Dangane da ko ALK sake tsarawa NSCLC yana da yuwuwar canjawa wuri zuwa kwakwalwa, bayanan suna da canji sosai. Nazarin ya gano cewa 3% na marasa lafiya tare da metastasis na kwakwalwa na NSCLC na iya ganin fassarar ALK kuma 11% na iya ganin haɓakawa. Wannan binciken ya nuna cewa adadin kwafin kwayoyin halittar ALK a cikin metastasis yana ƙoƙarin haɓaka, wanda zai iya kasancewa saboda zaɓin fa'idar ALK translocation tumor cells yayin metastasis.
Matsayin crizotinib a cikin ƙwayar kwakwalwa
Pfizer's crizotinib wani karamin kwaya ne mai hana yaduwar kwayoyi wanda Hukumar Abinci da Magunguna ta Amurka (FDA) ta amince da shi game da ci gaba da sake fasalin ALK na NSCLC, wanda ke kan ALK, MET da ROS tyrosine kinases. Ta hanyar hana ALK da MET tyrosine kinases, crizotinib zai iya hana tyrosine phosphorylation na kunna ALK.
Yawancin karatu ciki har da kwatanta crizotinib tare da daidaitattun tsarin maganin chemotherapy ga marasa lafiya tare da ci gaba na ALK da aka sake tsarawa NSCLC sun nuna cewa tsohon yana da mafi kyawun ci gaba mai sauƙi, ingantaccen ƙwayar cuta, da kuma yanayin rayuwa gaba ɗaya. Sauran nazarin sun nuna cewa gaba ɗaya maƙasudin tasiri na intracranial da ƙimar kula da cututtuka na crizotinib a makonni 12 sun kasance 18% da 56%, bi da bi; Tsakanin lokacin ci gaba na intracranial bayan aikace-aikacen wannan magani a cikin marasa lafiya da ba a kula da su ba shine watanni 7. Kula da cututtukan intracranial a cikin makonni 12 yana kusa da raunin tsarin.
Effectivenessaƙƙarfan tasiri da tsawon lokacin kula da marasa lafiya waɗanda a baya suka sami aikin rediyo na intracranial sun inganta. Effectiveididdigar tasirin cikin intracranial gaba ɗaya shine 33%, ƙimar sarrafa cutar a makonni 12 shine 62%, kuma lokacin tsakiyar zuwa ci gaba shine watanni 13.2. Yana da mahimmanci marasa lafiya da ke ci gaba da amfani da crizotinib sun ci gaba, amma gabaɗaya lokacin rayuwarsu ya fi waɗanda ba su ci gaba da amfani da maganin ba yayin ci gaba.
Kwanan nan, crizotinib azaman gwajin farko na gwajin 3 ya haɗa da marasa lafiya 79 waɗanda suka taɓa yin aikin rediyo don ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwa. Babban mahimmancin wannan binciken shine cewa an yiwa duk marasa lafiya magani da farko, kuma binciken PROFILE na baya ya nuna cewa radiotherapy na iya inganta inganci don haka ya ƙara jaddada tasirin intracranial da crizotinib ke haifarwa shi kaɗai.
Ilmin da ke da alaƙa game da daidaitawar kwakwalwar daidaitawar ALK ya fito ne daga rahotannin shari'a da nazarin rukunin ƙungiyoyin gwaji na asibiti. Lokacin nazarin waɗannan bayanan, yana da mahimmanci a yi la'akari da halayen marasa lafiya kamar yadda aka bayyana a cikin rahoton lamarin, saboda yawancin bincike sun haɗa da lokuta daban-daban ba tare da bambanci ba: alamun bayyanar cututtuka da asymptomatic metastases, pre-jiyya Magani da yawa irin su radiotherapy, magunguna daban-daban, da sauransu. iri daban-daban. A cikin nazarin masu hana masu hana ALK na ƙarni na biyu, ya zama dole a rarrabe ko an yi amfani da crizotinib a baya.
Bayanai sun nuna cewa tasirin intraranial na crizotinib ya bambanta. Yawancin marasa lafiya suna nuna bangaranci don kammala gafarar raunin ɓarna, amma ƙwayoyin CNS sun ci gaba, sabili da haka suna buƙatar shan magani ko la'akari da u
na magunguna na ƙarni na biyu.
Kodayake crizotinib yana da tasiri sosai, yawancin marasa lafiya tare da ALK-wanda aka sake tsara su NSCLC har yanzu zasu sami metastases ko ci gaba yayin magani. Karatuttukan farko sun nuna cewa CNS shine babban rukunin yanar gizo na gazawar magani yayin jiyya tare da crizotinib a kusan rabin marasa lafiya. Binciken da aka yi kwanan nan ya nuna cewa gazawar maganin CNS ana gani a cikin kashi 70% na marasa lafiya! Wannan ya faru ne saboda rashin karfin CNS na crizotinib, amma kuma saboda iyakantaccen yaɗuwa da aikin motsa jiki na P-glycoprotein.
Wani binciken ya ƙaddara ƙaddamar da ƙwayar magani a cikin ƙwayar ƙwayar ƙwayar cuta a lokacin maganin crizotinib a cikin marasa lafiya tare da ALK da aka sake gyara kwakwalwar ƙwaƙwalwar ƙwaƙwalwar huhu: 0.617 ng / mL, yayin da maida hankali a cikin magani shine 237 ng / mL. Bayani game da ci gaban cututtukan CNS shine cewa tsarin metastasis ya fi rikici fiye da farkon ƙwayar cuta, ko maye gurbi a cikin yankin crizotinib-binding.
Matsayi na ƙarni na biyu masu hana ALK a cikin ƙwayar metastasis
Ceritinib na Novartis shi ne ƙarni na biyu ALK-takamaiman tyrosine kinase mai hanawa wanda FDA ta amince da shi, kuma yana sa ido kan IGF-1R, mai karɓar insulin da ROS1. Ta hanyar wasu hanyoyin, ceritinib yana hana ALK autophosphorylation da kuma hanyar STAT3 mai nisa. A cikin binciken 1 na zamani, yawan tasirin marasa lafiya ba tare da crizotinib ya kasance 62%. Dangane da wannan, ana ci gaba da nazarin karatu na 2 na zamani kuma ana aiwatar da su.
Roche's alectinib ya riga ya sami izinin FDA don ci gaban da aka samu a magani. Nazarin ya gano cewa a cikin marasa lafiya tare da ALK sun sake canzawa NSCLC waɗanda ba a kula da su tare da crizotinib ba, ƙimar tasirin alectinib shine 93.5% (43/46 lokuta), kuma binciken da ya dace na 3 na yanzu yana gudana.
Nazarin ilimin kimiyyar kimiyyar zamani ya rigaya ya nuna cewa alectinib yana da mafi kyawun kwayar CNS fiye da crizotinib, kuma yawan kwayar CNS na maganin shine 63-94% na yawan kwayar. Wannan na iya kasancewa saboda alectinib ya bambanta da crizotinib da ceritinib, P glycoprotein ba shi da wani tasiri a kansa, kuma ba za a iya fitar da shi sosai daga yanayin intracranial ba.
A wani binciken da crizotinib-resistant marasa lafiya, 21 daga cikin 47 da marasa lafiya hada da suka asymptomatic kwakwalwa metastases ko marasa lafiya da kwakwalwa metastases amma babu magani, 6 marasa lafiya cimma cikakken gafarar bayan alectinib, 5 Daya haƙuri cimma m gafarta musu da takwas marasa lafiya da karko da siffofin maruran.
A cikin wannan binciken, marasa lafiya 5 sun yi gwajin azzakari cikin jiki kuma sun gano cewa akwai alaƙar linzami tsakanin magani da ƙwayar ƙwayar ƙwayar ba tare da haɗin kwayoyi ba. An yi tsammani cewa mafi ƙarancin taro a cikin ruwa mai ruɓar ciki shine 2.69 nmol / L, wanda ya zarce rabin ƙarancin hanawar masu ƙyamar ALK da aka ruwaito a baya. A kashi na biyu na binciken, marasa lafiya 14 da ba su sami crizotinib ba sun sami kulawa tare da alectinib, kuma marasa lafiya 9 sun tsira ba tare da ci gaba ba fiye da watanni 12.
Wani magani mai nasara wanda FDA ta amince dashi, ARIAD Pharmaceuticals 'brigatinib bawai kawai yana hana ALK bane, amma kuma yana kan EGFR da ROS1. Wani bincike da aka gudanar kan magungunan ya nuna cewa 16 daga cikin marasa lafiyar da ke jure wa crizotinib sun riga sun kamu da cutar ta intracranial metastasis lokacin da suka fara maganin, kuma 4 daga cikin wadannan marasa lafiya 5 sun nuna hoto bayan sun sha maganin. tasiri.
Akwai ƙananan karatu a kan ayyukan CNS na masu hana magungunan tyrosine kinase na farko da na ƙarni na biyu, amma akwai gwaji na 3 na bazuwar yanayi da yawa.
Matsayin masu hana ALK a cikin Pial Metastasis
Akwai 'yan karatun da ake yi a kan larurar meningeal metal a cikin raunin sake alkibla na ALK saboda mummunan hangen nesa da kuma wahalar kidaya tasirin maganin. Wasu mutane sunyi nazarin shari'ar 125 na NSCLC na meningeal metastasis kuma sun gano cewa rayuwa gabaɗaya bayan ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar kwakwalwa (WBRT) ba ta inganta ba, amma lokacin rayuwa bayan subarachnoid chemotherapy ya fi tsayi.
A cikin nazari na baya-bayan nan game da shari'o'in 149 na NSCLC na meningeal metastasis, rayuwar marasa lafiya gabaɗaya bayan subarachnoid chemotherapy, masu hana EGFR, da WBRT sun inganta. Har ila yau, akwai rahotanni kaɗan na shari'o'in da ke nuna cewa a cikin marasa lafiya tare da ALK waɗanda aka sake tsara surar ƙananan ƙananan meningeal, raunin intracranial a cikin marasa lafiya tare da crizotinib tare da yin amfani da subarachnoid na methotrexate sun inganta. Amma bayanan sun yi kadan kuma ba za a iya kammalawa ba.
Matsayin sauran magunguna na ƙarni na biyu a cikin ƙananan ƙwayar meningeal ba a kammala ba, amma tsarin da ake amfani da shi a halin yanzu tare da alectinib ko masu hana cin hanci na tyrosine kinase ya zama mafi tasiri.
Amincewa da juriya mai hana tasirin tyrosine kinase
Yawancin marasa lafiya na crizotinib sun sami juriya, kuma da yawa sun faru a cikin CNS. Anoƙarin haɓaka tasirin intraranial na crizotinib shine haɓakar haɓaka. A wasu rahotanni, an ƙara yawan ƙwayar crizotinib guda ɗaya daga 250 MG zuwa 1000 MG a cikin ƙa'idar tsarin; wasu an haɗa su da wasu magungunan yayin haɓaka crizotinib zuwa 600 MG.
A cikin ƙara yawan amfani, an inganta tasirin har zuwa wani mizani; bayani game da wannan shine crizotinib yana da adadi mai yawa, kuma hadewar magunguna yana inganta tasirin ƙwayoyin cutar ALK na sake shirya wasu magunguna.
Inhibarnoni na biyu masu haɓaka ALK na yanzu seritinib, alectinib da brigatinib suna da matsakaicin tasiri na 58-70%. Bincike ya nuna cewa wasu maye gurbi wadanda suke sa masu hana maganin tyrosine na ƙarni na biyu juriya na iya fuskantar wasu masu hana maganin tyrosine kinase.
Akwai shaidar cewa haɗin EML4-ALK yana da alaƙa da Hsp90, wanda ke taka muhimmiyar rawa wajen haɓaka nau'ikan ciwace-ciwacen ƙwayoyi. Kwayoyin sake tsarawa na ALK NSCLC, kamar su ganetespib, AUY922, retispamycin, IPI-504 da sauran magunguna, na iya haifar da apoptosis da ci gaba da ƙari ta hanyar lalata furotin haɗin ALK.
Haɗin hadewar crizotinib da IPI-504 na iya riga ya sami sakamako mai matukar tasiri na raunin kumburi. Bugu da kari, kwayoyin cututtukan crizotinib masu juriya suma sun nuna dawwama a hankali ga masu hana Hsp90. A halin yanzu akwai matakan Phase 1 da Phase 2 na gwaji.
Don shawo kan juriya na crizotinib, akwai kuma tsare-tsaren don ƙasa ko wasu hanyoyin kunnawa. Misali, akwai karatuttukan da suka danganci mTOR, PI3K, IGF-1R, da dai sauransu. Ana sa ran fasahar tsara tsara mai zuwa zata bunkasa wasu fasahohin yaki da miyagun kwayoyi da karin gwaje-gwaje akan kinase-dependent kinase, aurora kinases da epigenetic regulators.
Daidaita masu hana ALK don inganta haɓakar CNS ko aiki
Masu hanawa na ALK na ƙarni na biyu tare da keɓaɓɓun kaddarorin na iya ƙetare shingen ƙwaƙwalwar jini, don haka zaɓaɓɓu don magance matsalar ƙara yawan kwayar a cikin CNS. A cikin samfurin linzamin kwamfuta, yanayin tasirin X-396 a cikin kwakwalwa yayi daidai da crizotinib, X-396 na iya kai wa ga kusan sau huɗu rabin ƙarfin hanawa a cikin ruwa mai yaɗuwa, kuma yawan crizotinib a cikin ruwa mai kwakwalwa shine Rabin da rabin hanawa taro! Effarin inganci na X-396 na iya haɗuwa da ions hydrogen da ƙara tasirin intracranial a daidai lokacin da aka haɗa su tare da ALK.
X-396 a halin yanzu yana fuskantar gwaji na asibiti don tantance ko yana da tasiri a asibiti. Tsarin wasu magunguna na ƙarni na biyu yayi kama da na X-396, kuma yawan kwayar halittar jini-plasma na ƙwayoyin ma ya karu, wanda zai sami sakamako mafi kyau akan ciwan ciki.
A ka'ida, akwai hanyoyin da za'a kara karfin kwayar cutar ta CNS ta hanyar rage kwayar halittar, kara yawan mai mai narkewa, da gyara ta don kaucewa ɗaure ga sunadarai masu yaduwa na yau da kullun akan shingen kwakwalwar jini. Alectinib yana da tasirin CNS mai ƙarfi saboda rashin ƙarfi ga P glycoprotein. Wani mai hana ALK na ƙarni na biyu PF-06463922 an tsara shi don kaucewa fitowar sa a shingen ƙwaƙwalwar jini da farfajiyar ƙari kuma musamman haɓaka haɓakar CNS da ƙari. Ka'idar ita ce
don rage nauyin kwayoyin, kara yawan narkewar mai, Ya canza adadin alakar hydrogen.
Sake tsara shingen kwakwalwar jini don haɓaka yawan aiki
Wata hanyar da za a bi don kara karfin ruwan magani na kwayar cuta ita ce ta kara yaduwar karfin kwakwalwar jini. Kamar yadda aka ambata a baya, shingen kwakwalwa na kwakwalwa yana da aiki mai tasiri da aiki: P glycoprotein shine babban abin da ke cire abubuwa cikin rayayye. Sabili da haka, ɗayan mafita shine hana ɗaukar P glycoprotein zuwa magani.
A cikin samfurin linzamin kwamfuta, ƙari na elacridar na iya sanya crizotinib cikin intracranial har sau 70 bayan awanni 24, kuma ƙwayar plasma abu ne na al'ada, wanda yana iya zama saboda jikewar shawar intracranial. Tunda tasirin tasirin magungunan yana da kyau, ya kamata a yi la’akari da gwajin ɗan adam, kuma ya kamata a mai da hankali ga nazarin a haɗe tare da ceritinib da sauran magunguna.
Wata hanyar bincike kuma tana mai da hankali ne kan kinin vasoactive, kamar aikace-aikacen analogues na kinin don daidaita shingen kwakwalwar jini ta hanyar prostaglandins da nitric oxide. Gwaje-gwajen dabbobi sun nuna cewa wannan tsarin na iya ƙara yawan ciwan CNS na magani da haɓaka rayuwa gabaɗaya. Kinin Vasoactive haɗe tare da masu hana ALK na iya haɓaka jikin intracranial, kuma ana iya yin bincikensa da yawa ta hanyar samin ruwa ko kuma maganin asibiti.
Daidaitawa na ƙananan ƙwayoyin cuta
Shaidu masu mahimmanci sun nuna cewa ƙwayoyin ƙwayar ƙwayar cuta suna iya mamaye ƙananan ƙwayoyin microenvironments kamar su jijiyoyin jini, tasoshin lymphatic da matrix extracellular. Wannan mawuyacin yanayin na ƙara haɓaka ciwace-ciwacen ƙwayoyin cuta, ƙaddarar fata, da juriya na jiyya, wanda ke da mahimmanci ga maye gurbi da ke haifar da ƙarin metastases.
Theoryaya daga cikin ka'idoji shine daidaita al'amuran ilimin lissafi na ƙoshin lafiya zai iya inganta hangen nesa na mai haƙuri. Oneaya daga cikin mahimman manufofin daidaitawa shine ma'amala da rikitaccen tsarin jijiyoyin jiki. Magungunan jijiyoyin jijiyoyin jini sun ragu, wanda ke rage maganin ya kai ga nama wanda ake so kuma ya haifar da hypoxia na cikin gida. Hypoxia ba kawai yana ƙaruwa da ciwace ciwace-ciwacen ƙwayoyin cuta da ƙwayar cuta ba, amma kuma alama ce ta cin zafin kumburi kuma yana rage tasirin maganin-dogaro da oxygen kamar rediyo.
VEGF inhibitors have been used to reduce disordered angiogenesis and restore the vascular microenvironment. In the mouse glioblastoma model, the VEGF inhibitor bevacizumab reduces hypoxia and enhances the effect of radiotherapy. This type of benefit can also be seen in cytotoxicity treatment when blood vessels are normalized, but no studies have been conducted on the combination of ALK and VEGF inhibitors.
ALK ya sake tsara aikin NSCLC matsakaiciyar maganin ƙwaƙwalwar kwakwalwa
Shekarun marasa lafiya tare da cutar kumburin ALK ba su da yawa, wanda shine ɗayan mahimman batutuwan da za a yi la’akari da su yayin magance raunin ciki, saboda yawancin marasa lafiya har yanzu suna aiki, suna da yara ƙanana, kuma suna buƙatar kula da iyalansu. Wannan yana buƙatar kariya ga ayyukan fahimi, musamman mahimman ayyukan fahimi.
Tare da gano masu hanawa na ALK, an kirga tsawon rayuwar wadannan marasa lafiya a cikin shekaru, kuma ya kamata a ba da fifiko ga kulawar lokaci mai tsawo tare da ƙananan sakamako masu illa na dogon lokaci. Marasa lafiya tare da ALK da aka sake fasalin NSCLC sun daɗe suna rayuwa koda kuwa suna da metastases na ƙwaƙwalwa, wanda ke canza manufar magani daga sauƙin sauƙaƙe don kiyaye ƙimar rayuwa da aikin fahimtar marasa lafiya.
Saboda tsawon lokacin rayuwa, marasa lafiya da ƙananan metastases ana ba da shawarar sosai don yin la'akari da aikin rediyo na stereotactic, saboda WBRT zai lalata haɓakar ƙwaƙwalwar ajiya da tunawa da bayanai. Duk da haka, ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta tana buƙatar WBRT, wanda zai iya zama damar yin amfani da shingen kwakwalwar jini da ya lalace kuma a lokaci guda ana amfani da magungunan da aka yi niyya don ƙara yawan ƙwayar cerebrospinal.
Akwai fewan bayanai kan illolin crizotinib waɗanda aka haɗa tare da aikin rediyo. Sabili da haka, marasa lafiya da ke karɓar crizotinib don raunin intracranial dole ne su dakatar da maganin aƙalla kwana 1 kafin aikin rediyo. A wasu marasa lafiya, an sake amfani da crizotinib bayan rediyo a cikin kwakwalwa, kuma an gano cewa crizotinib har yanzu yana da tasiri ga raunin ɓarna bayan raɗaɗɗiyar rediyo, wanda kuma ya yi daidai da ƙarancin CNS na ƙwayoyi kafin aikin rediyo.
Karatuttukan sun bayar da rahoton cewa marasa lafiya tare da ALK sake tsarawa kwakwalwa metastases suna da matukar muhimmanci tsawon rayuwa bayan radiotherapy fiye da marasa lafiya da ALK daji-type. Wannan na iya faruwa ne sakamakon karuwar yaduwar cutar kwakwalwa-kwakwalwa da rage magana ta P-glycoprotein a cikin makonni na aikin radiotherapy. Duk da yawan haɗarin illolin da ake samu daga maganin haɗuwa, yana da sauƙi don gudanar da nazarin ilimin haɗin gwiwa tare da ƙananan sakamako masu illa na masu hana ALK, kuma haɓaka haɓakar haɓaka bayan radiotherapy na iya ci gaba da niyya.
Batun da za a jaddada shine jerin hanyoyin maganin da aka yi niyya da kuma aikin rediyo. Nazarin daban-daban masu alaƙa sun nuna cewa masu hana ALK na iya amfana daga ci gaba da aikace-aikace, amma babu kwatankwacin masu hana ALK daban. Nazarin ya nuna cewa amfani da crizotinib bayan WBRT na iya inganta kulawar raunin intracranial. A ƙarshe, bayanan suna nuna cewa ana iya ba da shawarar masu hana ALK bayan aikin rediyo, kuma yana iya inganta ingancin magani.
Jagorori da kwatance na gaba
A lokuta na ci gaba ko metastasis na kwakwalwa, tattaunawa da yawa da suka shafi oncology, radiotherapy, neurosurgery, da dai sauransu suna buƙatar la'akari. Cibiyar Kula da Ciwon Kankara ta Kasa ta ba da shawarar cewa marasa lafiya da ke fama da cututtukan kwakwalwa na asymptomatic suna buƙatar amfani da crizotinib shi kaɗai. Don ci gaba da raunuka na ciki, SRS ko WBRT ya kamata a yi la'akari da lokacin da akwai alamun bayyanar cututtuka, sa'an nan kuma amfani da masu hana ALK. Idan za a iya magance cutar tare da SRS, ya kamata a ba da la'akari don guje wa duk aikin rediyo na kwakwalwa don kada ya shafi aikin tunani.
Jagororin sun ba da shawarar cewa har yanzu ana iya amfani da crizotinib ko ceritinib a cikin marasa lafiya tare da ci gaban asymptomatic. Rahotannin shari'ar sun nuna cewa tsawon rayuwar rashin ci gaba ya banbanta tsakanin crizotinib da radiotherapy bayan radiotherapy. Amfani da masu hana ALK na ƙarni na biyu ya kamata su ƙarfafa likitoci suyi amfani da waɗannan magungunan yayin da cutar ke ci gaba don haɓaka maganin intracranial.
Saboda babban yuwuwar komawa cikin intracranial lokacin amfani da masu hana ALK, ana buƙatar gwajin MRI akai-akai bayan aikin rediyo don tantance ci gaban metastases. Don metastases na WBRT, ana ba da shawarar yin MRI kowane watanni 3. Tabbas, sake fasalin ALK zai amfana da shi.
Idan metastasis ya kara tsananta, likita ya kamata ya canza mai hana ALK da aka yi amfani da shi, kuma idan bayyanar cututtuka ta bayyana, ya kamata a sake haskaka su; ta mahangar rarar fa'idodi, har yanzu sun fi son a sake ba su magani. Don ALK ya sake jujjuya raunin ciki, idan rediyo tare da masu hana ALK ci gaba, haɗuwa da pemetrexed alama shine mafi kyawun zaɓi.
Gyarawar ALK da aka yiwa masu hanawa don shawo kan juriya da magungunan ƙwayoyi, inganta haɓakar sa ga CNS, da haɓaka ƙarfin ƙarfin da tasirin sa bayan cimma burin, ƙarin bincike akan wannan. Nan gaba kadan, narkar da wadannan kwayoyi a cikin CNS zai fi girma kuma ana iya amfani da su bi da bi lokacin da juriyar maganin intracranial ta bayyana.
Tare da karuwa a cikin hanyoyin gwajin DNA na samuwa, ana iya ba da shawara ga marasa lafiya su maimaita biopsies don tantance tsarin juriya na miyagun ƙwayoyi yayin da suke ci gaba, wanda zai jagoranci aikace-aikacen asibiti na masu hana tyrosine kinase waɗanda suka fi tasiri.
Kammalawa
Metididdigar ƙwayar ƙwayar ƙwayar cuta ta kwakwalwa yana ƙaruwa. Ofaya daga cikin shirye-shiryen don haɓaka inganci shine yin kasida game da cututtukan cututtukan ƙwayoyin cuta na musamman, kamar su ALK sake shiri. A cikin marasa lafiya w
ALH ya sake gyara kansa na sankarar huhu, crizotinib ya nuna ya fi na kimotir magani, amma sarrafawar raunin intracranial har yanzu bai dace ba. Wannan matsalar, da bayyanar maye gurbi masu alaƙa da tasirin crizotinib, sun haifar da fitowar yawancin wakilai masu adawa da ALK na ƙarni na biyu waɗanda ke aiki a kan hanyoyi daban-daban ko ƙara haɓakar shingen kwakwalwa-jini.
A cikin shirye-shiryen anti-ALK na ƙarni na biyu, kamar su ceritinib, kodayake P glycoprotein har yanzu yana ɗan fitar da shi waje, ya nuna cikakken iko na raunin intracranial. Sakamakon intracranial ya dogara da ingancin magani da ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar jini na iya samun wasu abubuwan da ba a bayyana ba.
Saboda magungunan da aka yi niyya da ALK sababbi ne, har yanzu akwai ƙaramin bincike game da haɗuwa da wannan maganin da kuma maganin rediyo a cikin yanayin ƙwaƙwalwar kwakwalwa, amma wannan ma ɗayan mahimman shirye-shirye ne masu tasiri a cikin maganin haɗin gwiwa. A ƙarshe, an bayyana cewa marasa lafiya tare da gyaran ALK NSCLC na iya rayuwa tsawon rai bayan fa'idantar da sabbin magungunan da aka yi niyya.
Dangane da fahimta da aiki na cututtukan cututtukan CNS, ana buƙatar ci gaba da bincike kan sababbin zaɓuɓɓukan magani don magance matsalolin ingancin rayuwa da hangen nesa na aiki. Hakanan akwai buƙatar gaggawa don nazarin hanyoyin jure magunguna. Tabbas, abu na farko da yake da mahimmanci shine likitoci su karfafa nazarin marasa lafiya tare da kwakwalwar kwakwalwa don fayyace lokaci mafi kyau don aikace-aikacen masu hana maganin tyrosine kinase na farko da na biyu a cikin marasa lafiyar NSCLC, da kuma mafi kyawun lokaci don kwakwalwa radiotherapy.
