TAP CHi Y HOC VIJT NAM TAP 459 - THANG 10 - SO 1 • 2017 '. KET LUiOkN
Nghien ciTu tai Khoa Ung bu'du BV ™ H H giai toan 09/2015 - 09/2016 vdi thang do EORTC JLQ-C30 de tai ghi nhan CLS ciia NB BCMDT d niTc trung binh vdi cac phu'dng dien chiTc nang lat miTc kha va tdt. Trong qua trinh dieu tri, NB hu'dng gap khd khan ve tai chinh, trai qua cae rieu chiTng met mdi, mat ngii, mat cam giac igon mieng va dau. Cae yeu t d anh hu'dng den :LS ciia NB bao gom gidi tinh, nhdm tudi, tinh rang hdn nhan va trinh dp hpc van.
FAI UEU T H A M KHAO
L. Bui Vu Binh. '^Khao sit chat iu'tina cuoc sdnp cua naWdi benh una thi/ va mot so yeu to anh hudna tai benh vien dai hoc Y Ha Noi 2016, luan an thac sT y khoa, trUdng dai hoe Y Ha Noi, Ha Noi.
z. Nquven Van Tuan. '•^Phu'dnq phip Udc tfnh cd mau cho mot nqhien cull v hod'.
3. "Chronic myeloid leukaemia statistics". Cancer Research UK. Retrieved28 October 2014.
4. "What are the key statistics about chronic myeioid leukemia?", www.eancer.orq. Amencan Cancer Societv. Retrieved 6 January 2015.
5. Chronic Myelogenous Leukemia Treatment fPDO®) General Information About Chronic Mveloaenous Leukemia f2015).
o. Fabio Efficace (2010),""Health-related quaiitv of life in chronic myeioid leukemia patients receivinq lona-term therapy with imatinib compared with the qeneral populatlod'. 52nd Annual Meeting of the American Society of Hematology, Orlando, FL, December. 4-7.
7. Roxanne Nelson (20131, "TAT therapy affects quality of Life in CML patients. Care Cancer.
2013;21:1097-1103.
KET QUA XET NGHIEM TINH DA HINH GEN DPYD TAI BENH VIEN BACH MAI
rOM TAT
Muc tieu nghien edu: Xac dinh tinh da hinh gen 3PYD tren benh nhan ung thu" cd ehi dinh dieu tri 5- 'U tai Benh vien Bach Mai. Boi tddng va phu'dng ohap nghiSn edu: 139 benh nhan du'dc chan doan rac djnh ung tiiu' co chi d|nh dieu tri bang 5-FU du'dng iem tmyen hoac uong, dUdc xet nghiem tinh da hinh )en DPYD dUa fren bd 'kit PGX-5FU StrlpAssay'"
yiennaLab 4-^720). Kei gua: Tat ea eac benh nhan leu CO kieu gen DPYD binh_thUdng, khong phat hien inrdng hdp nao ed bien the gen DPYD lien quan den Joe tinh cua 5-FU.
Tdkhoa: Ung thu', 5-FU, doc ti'nh, da hinh DPYD SUMMARY
RESULT OF Z7PW> POLYMORPHISM I N CANCER PATIENTS AT BACH M A I HOSPITAL
Objective. To determine DPYD polymorphism in ancer patients with 5-FU treatment at Bach Mai Hospital. Patients and Methods. 139 diagnosed ancer patients, who were later treated with oral, njection or infusion of 5-FU regimen. These patients vere analyzed their DPYD gene polymorphism by jsing the PGX-5FU StrlpAssay'" kit (ViennaLab).
Results. All patients had normal DPYD genotypes;
my DPYD variants associated with 5-FU toxicity has )een detected.
Key words. Cancer, 5-FU, toxicity, DPYD Jolymorphism
*Tt Yhoc hat nhan va ung bddu^ Benh vien Bach Mai
^hiu fraeh nhiem chinh: Pham Cam Phu'dng Email: [email protected] Jgay nhan bai: 23.7.2017 Jgay phan bien khoa hoc: 5.9.2017 Jgay duyet bai: 15.9.2017
Mai Trong Khoa*, Pham Cam Phirong*
I. DAT VAN e l
Ung thiT la benh ly ac tinh eiia te bao. Oieu tri ung thu' la dieu tri da md thiTe, phdi hdp nhieu phu'dng phap, trong dd 3 phu'dng phap chinh la:
phau thuat, hda chat va xa trj. Phau thuat va xa trj la cac phuWng phap dieu trj tai eho, tai viing.
Hda chat la phu'dng phap dieu tri toan than [1].
Cd nhieu loai hda chat du'dc sir dung trong di§u trj benh ung thu*, trong dd 5-flourouracil (5- FU) la mdt trong eae hda chat nen trong nhieu phac do hda tri benh ung thu' nhu' ung thu" dai triTc trang, ung thu* da day, ung thiT thiTc quan, ung thu' vu,... Mdt sd nghien ciTu cho thay mu'e dp ddc tinh ciia 5-FU lien quan tdi gen DPYD (dlhydropyrlmidine dehydrogenase^, gen ma hda protein tham gia vao qua trinh chuyen hda 5-FU d gan, nen anh hu'dng tdi kha nang dao thai 5- FUd ngu'di benh [2].
5-FU bi dao thai manh d gan bdi hoat tinh cua enzyme dlhydropyrlmidine dehydrogenase (DPYD). Nhu'ng benh nhan kieu gen dj hdp (mang mot dot bien gen DPYD tren cap nhiem sac the, chiem khoang 3-5%) cd kha nang dao thai 5-FU kem hdn ngu'di benli nhan ed kieu gen binh thu'dng tdi 30-70%. Do dd, neu sir dung lieu thdng thu'dng thi dpc tinh 5-FU tren nhiJng benh nhan nay se cao hdn rat nhieu so vdi nhu'ng benh nhan binh thu'dng. Theo khuyen cao cap nhat thang 05 nam 2014 ciia Quy u'dc thiTc hanh lam sang Du'dc di truyen (Clinical Pharmacogenetics Implementatipn Consortium -
143
VIETNAM MEDICAL JOURNAL N°1 - O C T O B E R - 2 0 1 7 : P I C ) thi nhuiig ngu'di mang kieu gen di hdp nen
Jieu tri 5-FU (nhu" Tegafur, Capeeitabine) vdi leu khdl dau thap hdn it nhat 50%, nhu'ng lieu :iep theo can giam tiiy theo ddc tinh tren benh ihan cu the. Neu benh nhan mang ca 2 ban sao :iia gen bj ddt bien (dong hdp dot bien, chiem dioang 1%) dan tdi thieu hut hoan toan enzyme 3PYD va benh nhan can du'dc chuyen sang lu'dng dieu trj khac. Do vay, xet nghiem tinh da linh gen DPYD can phai du'dc thdc hien tren :enh nhan tru'dc khi dieu tn bang 5-FU, tuy ihien tai Viet Nam chu'a ed nghien ciTu ve ty le Jdt bien gen DPYD. Vi vay ehiing tdi tien hanh nghien ciTu nay nham muc tieu: Nhan xet ket :iua xet nghiem tinh da hinh gen DPYD tren benh nhan ung thu' ed chi dinh dieu trj 5-FU tai Benh i/ien Bach Mai.
II. OOI Tl/pNG VA PHL/aNG PHAP NGHIEN CU'U Doi tu'dng nghien cu'u: 139 benh nhan dUdc chan doan xac dinh ung thu' cd chi djnh dieu trj bang 5-FU du'dng tiem truyen hoac udng, du'dc xet nghiem tinh da hinh gen DPYD tai Ddn vj gen tn lieu, Trung tam Y hpc hat nhan va ung bu'du - Benh vien Bach Mai.
Phu'dng phap nghien cuij: Nghien culi md ta - Thu thap cae dac diem benh nhan du^ vao mot mau thu thap thdng tin thdng nhat, bang each phdng van triTc tiep benh nhan/ngu'di nha benh nhan va tham khao hd sd benh an.
- Quy trinh thu'c hien ciia ky thuat du'a tren bp kit PGX-5FU StrlpAssay'" (ViennaLab 4-720) gom 4 giai doan ehinh:
+ Tach DNA tir mau mau
+ Khueeh dai doan gen quan tam bang phan u'ng PCR
+ Lai san pham khueeh dai vdi dau dd dac hieu du'dc phan bo tren Teststrip
+ Phan tich ket qua bang each so sanh each vach tren Teststrip vdi thang chuan
- Xif ly sdi lieu: sOrdung phan mem SPSS 16.0.
Thdi gian nghien cuXi: TiT thang 12/2016 den thang 7/2017.
fiia diem nghien cu'u: Ddn vj Gen - Te bao goc, Trung tam Y hpc Hat nhan va Ung bu'du, Benh vien Bach Mai.
III. KET QUA NGHIEN CU'U 1 . Dac diem b i n h nhan Bang 3.1. Tuoi bSnh nhan
Yeu to Tuoi
Tieu chi
<40 4 0 - 6 0
> 6 0 Tonq
n l b hi hi 1J9
Tv le{«/o) 10,8 41,0 48,2 100
Tuoi trung binh Tuoi Idn nhat Tudi nhd nhat
57,3 ±12,4 91 25 Nhin xet: Tuoi trung binh la 57,3 ± 12,4 nhd niiat 25, cao nhat: 9 1 . Benh hi^m gip 6 ngu'di tre tuoi, ehi cd 15/139 benh nhan diTdl 40 tudi (chiem 10,8%).
44,6
55,4 % a Nam
Bieu dd 1. Gidi tlnh Nhan xet: Benh nhan nam gap nhieu hdn niJ, 55,4% so vdi 44,6%. Ty le nam: nCi' la 1,25:1. ^'
Bang 3.2. Cae loai benh ung thd Chan doan
Ung thu" da day Ung thu' dai trang Ung thu" trUc trang Ung thu' gan Unq thu' phoi U ^ thu' thu'c quan
Unq t h u vu Unq thu' CO tu' cunq
Tong
n 30 67 32 2 2 4 1 1 139
TylS{%) 21,6 48,2 23,1 1,4 1,4 2,9 0,7 0,7 100 Nhan xet: Benh nhan ung thu' dai trang chiem ty le cao nhat la 48,2%. Ung thu' da day va ung thii' tru'c trang it gap hdn vdi t / le tu'dng iTng la 21,6% va 2 3 , 1 % .
2. Xac ^ n h tinh da hinh gen DPYD Bang 3.3. Xet nghiem gen DPYD
Tieu chi Binh thi/dng Di hcjp dot bien Don hdp dot bien
n 139
57 0
T'i'lc(»/o) 100
0 0 Nhin xet: Tat ea cac benh nhan du'dc xet nghiem tinh da hinh gen DPYD deu eho ket qua binh thu'dng.
IV. BAN LUAN
Hda chat la phu'dng phap dieu trj ehinh trong ung thu' du'dc chi djnh trong hau het cac giai doan benh. Hda chat la chat gay dpc te bao do vay ngoai hieu qua dieu tri cung cd nhieu dpc tinh gay ra cac tac dung phu nghiem tn?ng. Co nhieu loai hda chat du'dc sir dung trong dieu trj benh ung thu", trong do 5-flourouracil (5-FU) la m5t trong cae hda chat nen trong nhieu phac d6 hoa trj benh ung thu' nhu" ung thu" dai tru'c trang, ung thi/
da day, ung thu'thiTc quan, ung thu" vu,...
TAP CHl Y HOC VigT NAM TAP 459 - THANG 10 . SO 1 - 2017 Cd che tieu diet te bao ung thd ciia cac hda
chat 5-FU: Khi vao cd the ngu'di benh thi 5-FU chuyen hda thanh fluorodeoxy uridine monophosphate (FdUMP) la chat de che thymidylate synthetase gay thieu thymine eho qua trinh tdng hdp DNA, lam cho te bao ung thu' bj tieu diet. FdUI^P cung cd the chuyen hda tlianh fluorodeoxyuridine triphosphate (FdUTP) canh tranh lam dirt gay DNA. Tu'dng td, fluorouridine triphosphate (FUTP) hinh thanh IILT 5-FU lam dirt gay RNA.
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Hinh 2. Cd chetiSu diet tebio ung thd cua cac hoa chat S-FU
5-fluorouraeil (5-FU) cd the du'dc chuyen hda thanh fluorouridine monophosphate (FUMP) thdng qua fluorouridine (FUR), sau dd phosphcryl hda thanh fluorouridine diphosphate (FUDP), tir dd phosphoryl hda thanh fluorouridine triphosphate (FUTP) gay dut gay RNA, hoac chuyen thanh fluorodeoxyuridine diphosphate (FdUDP). FdUDP ed the chuyen thanh fluorodeoxyuridine triphosphate (FdUTP), hoac chuyen thanh fluorodeoxyuridine monophosphate (FdUMP) dc che enzyme thymidylate synthetase (TS), deu gay dd:t gay DNA. Mdt con du'dng hoat dpng khac ciia 5-FU la chuyen hda thanh fluorodeoxyuridine (FUDR), sau dd du'dc phosphoryl hda thanh FdUMP, tiT do tac ddng nhu" con du'dng tren. 5-FU dddc dao thai bang each chuyen hda thanh dihydrofluorouracil (DHFU) bdi enzyme dihydropyrimldine dehydrogenase (DPYD), qua trinh nay dien ra nhieu nhat d gan, len den 80%.
Cac enzyme chuyen hda: OPRT orotate
phosphorlbosyltransferase; PRPP - phosphoribosyl pyrophosphate; UP - uridine phosphorylase; UK - uridine kinase; RR - ribonucleotide reductase; TK - thymidine kinase [6].
Dpc tinh thu'dng gap ciia 5-FU la: chan an, budn ndn, giam eae ddng te bao mau (bach cau,' tieu eau, hong eau), viem rudt, viem gan, viem phdi ke...Mpt sd nghien eiTu cho thay miTc dp ddc tinh ciia 5-FU lien quan tdi gen DPYD (dihydropyrimldine dehydrogenase^), la gen ma hda protein tham gia vao qua trinii chuyen hda 5-FU d gan, nen anh hu'dng tdi kha nang dao thai 5-FU d ngu'di benh. 5-FU bj dao thai manh d gan bdi boat tinh eiia enzyme dihydropyrimldine dehydrogenase (DPYD). Nhij'ng benh nhan kieu gen di hdp (mang mdt dot bien gen DPYD tren cap nhiem sac the, chiem khoang 3-5%) ed kha nang dao thai 5-FU kem hdn ngu'di benh nhan ed kieu gen binh thu'dng tdi 30-70%. Do do, neu sir dung lieu thdng thiTdng thi dpc tinh 5-FU tren nhii'ng benh nhan nay se cao hdn rat nhieu so vdi nhu'ng benh nhan binh thu'dng. Theo khuyen cao cap nhat thang 05 nam 2014 ciia Quy u'dc thiTc "hanh lam sang Du'dc di truyen (Clinical Pharmacogenetics Implementation Consortium - CPIC) thi nhij'ng ngu'di mang kieu gen dj hdp nen dieu tri 5-FU (nhu' Tegafur, Capeeitabine) vdi lieu khdi dau thap hdn it nhat 50%, nhu'ng lieu tiep theo can giam tiiy theo ddc tinh tren benh nhan eu the. Neu benh nhan mang ea 2 ban sao ciia gen h\ dot bien (ddng hdp dot bien, chiem khoang 1%) d i n tdi thieu hut hoan toan enzyme DPYD va benh nhan can du'dc chuyen sang hu'dng dieu trj khac.
Theo nghien eiTu eiia chung tdi tat ca cac benh nhan dUde xet nghiem d^u cd kieu gen DPYD binh thu'dng, khdng phat hien bat cir tru'dng hdp nao cd thay ddi kieu gen lien quan den dpc ti'nh khi sd dung 5-FU. Cae nghien euTu khac tren the gidl eiJng cho thay ty le ed dot bien tren gen DPYD rat thap. Mot nghien cu'u khac ciia Lunenburg (2016) tren 275 benh nhan da trang du'dc dieu tri fluoropyrimidine cd 14 tru'dng hdp (5,1%) phat hien bien the gen DPYD va du'dc khuyen eao giam lieu dieu tri xuong 25- 50% va cac benh nhan nay khdng phat trien doe tinh sau khi du'dc giam lieu dieu tn [3]. Nghien eiru ciia Eiraiyahi (2016) tren 588 benh nhan khu VlTc Ddng Phi khdng phat hien tru'dng hdp nao ed bien the tren gen DPYD [4]. ^
Do ty le phat hien bien the tren gen DPYD lien quan den ddc tinh ciia 5-FU rat thap do vay chiing tdi khdng khuyen cao tiep tuc tien hanh xet nghiem nay tru'dc dieu t n .
VIETNAM MSDICAL JOURNAL H°1 - OCTOBER - 2017
Hinh 3. Kha nang dap dng thude eua cac benh nhan ed kieu gen DPYD khac nhau [6]
V. KET LUAN
Tat ea 139 benh nhan du'dc xet nghiem tinh da hinh gen DPYD deu cd kieu gen binh thu'dng.
T A I UEU THAIVI KHAO
1. Nguyen Van Hieu (2015). Ung thU hoc. Nha xuat ban Y hpc. Ha Noi
2. Mai Trong Khoa (2016]l. Khang the ddn dong va phan tir nhd trong dieu trj benh ung tiiU. Nha xuat ban Y hoc. Ha Noi.
3. Lunenburg CA, Staveren MC Gelderblom H (2016). Evaluation of clinical implementation of prospective DPYD genotyping in 5-fluorouradl- or
capecitabine-treated patients Pharmacogenomles. 2016 May;17(7):721-9
4. EIraiyah T, Jerde CR, Shrestha S (2016). Novel Deleterious Dihydropynmidine ^ Dehydrogenase Variants May Contnbute to .i^- Huorouracil Sensitivity in an East Afhcan Populaton Clin Phannaeol Ther. 2017 Mar;101 (3): 382-390 '• ' 5. Morel A, Boisdron-Celle M, Fey L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nudeotide polymorphisms on 5-fluorouracil tolerance. Moi Cancer Ther. 2006;5(11):2895-2904.
b. Offer SM, Wegner NJ, Possum C, Wang |^
Diasio RB. Phenotypic profiling of DPYD variations relevant to 5-fiuorouraal sensitvity using real-time cellular analysis and in vitro measurement of enzyme activity. Cancer Res, 2013;73(6): 1958-1968.
/ . Boisdron-Celle M, Remaud G, Traore S, et al.
5-fluorouraeil-related severe toxicity: a compaH|fflB of different methods for the pretherap^^w detection of dihydropyrimidine dehydrbgeiil^P deficiency. Cancer Lett. 2007;249(2):271-282 V
DANH GIA KET QUA BlfaC DAU P H A U THUAT DIEU TRI U MO DEM DU'CTNG TIEU HOA
T O M TAT
Mi|c tieu nghien cu'u; Mo ta dac diem lam sang, can lam sang va danh gia kit qua sdm eua dieu tri phau thu|t u mo dem du'dng tieu hda. PhUdng phap: nghien culi mo ta hoi ciTu ket hcfp tien ciTu.
B&nh nhan dUde chon nghjen ciTu la nhuhg benh nhan CO chan doan hoa md mien dich la u md dem dudng tieu hoa, dUde phau thuat tai benh vien K tiT 8/2013- 11/2015. K ^ qua: Cd 43 benh nhan bao gom 22 nu"
va 21 nam, tudi trung binh la 51,9. Tien sir md cij chiem 20,9% (du'dc md UMDDTH tai dja phu'dng).
Bleu hien lam sang rat da dang va khong dac hieu.
Trieu chimg thu'dng gap nhat la dau bung (60,5%) va sd thay u bung (52,8%). Co 69,8% dUdc ngi soi (noi soi da day 24 benh nhan va noi soi dai trUc trang 6 benh nhan). Sieu am cd the gOi y UMDDTH trong 90,7% trUdng hcfp. Ti le phat hien du'Oc ton thu'dng gdi y UMDDTH khi chup cat Idp vi tinh la 100%.Ty leUMDDTH da day,ru6t non, dai trang, trUc trang lan lutrt la^55,5%, 25,6%, 9,3%, 9,3%.Ty le mo npi soiho tni/mo md la 3/43 (6,9%) benh nhan,ty le phau thuat
*Benh viin K
Chiu trach nhiem ehinh: Pham van Binh Email: [email protected] Ngay nhan bai: 11.7.2017 Ngay phan bien khoa hpc: 6.9.2017 Ngay duyet bai: 13,9.2017
Pham van Binh*, Tran Dinh Tan*
triet can (RO) la 88,4% va phau thuat lay u toi da (R2) chiem 11,6%. Chi coltru'dng hdp du'dc vet hadila UMDDTH d da day ton thu'dng phai cat doan d^ day (ket qua bach cd di can). Thdi gian mo trung binh la 130 phiit (70-200 phut). Chi cd mot tn/dng h ^ diay mau trong mo do u xam lan dUde xu" tri cat them^ \id\
va du6i tuy c^m mau. Kich thUdc u trung binh la 8,2 cm, phan dp ac tinh chii yeu la dp thap (44,2%).TIra gian theo doi trung binh la 12 thang (01-27 thang]
chUa cd trUdng hop nao tiT vonp. Ket liian:_U mo dem dudng tieu hoa la loai benh it gap, bieu hien lam sang^khong dac hieu chii yeu la dau bung, ty sd thay u. Ton thUOng u tren CTcanner va sieu am o bung giiip gdi y chan doan UMDDTH. Vi tri u thUdng gSpd day day 55,5%, ruot non 25,6%, dai trang 9,3%, tnfl:
trang 9,3%. Phau thuat la phudng phap diSu tri hieu qua vdi ket qua sdm: ty le mo noi soi ho trd la 7%, mo md 93%, ty le cat u triet can ]R0) 88,4%, khong CO bien chu'ng va tiT vong sau mo, theo doi sau mo trung binh 12 thang ehu^ cd tu' vong
SUIVIMARY
EARLY RESULTS OF SURGICAL MANAGEMENT I N GASTRO-INTESTINAL STROMAL "TUMORS Patients and Methods: This is a retrospedrre and perspective description review of 43 patients who had GIST and underwent surgical management in National Cancer Hospital from 8/2013 to 11/201^
Results: There were 22 females and 21 males. The
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