Y HOC VI$T NAM THANG 7 - SO 1/2014
B i r a c DAU KHAO SAT CAC YEU T O DOC Lire CAGA, VACA
CCA HELICOBACTER PYLORI TREN BENH NHAN UNG THU* DA DAY
Tr3n Dinh Tri*, Ho Dang Quy Dung*, T r a n Thanh Binh*
Vu Van Khien**, Phan Quoc Hoan**
TOM TAT
Myc tieu: Khao sat cac yeu to doc li/c cagA, vacA cua Helicobacter pylori (H. pylori) phan lap tren benh nhan ung thi/da day (UTDD)
Doi tu'dng Vci phu'dng phdp; gom 127 benh nhan UTDD da di/^c chan doan noi soi, xet nghiem mH tal Benh vi^n Tmng u'dng Quan dpi 108 (Ha Npi) va B?nh vien 0\(f Riy (TP. Ho Chi Minh). Nghign ciiXi tien hdnh theo phuUng phdp nghien cirli mo ta cSt ngang, xu' ly so lieu bang phan mem SPSS 20.0.
Ket qua: 127 BN UTD, gom: nam: 77,2%
(98/127 ), niJ 22.8% (29/127), Nam/ni? =3,4. Tuoi trung binh la 63,2 (34 - 87tu6i). 100% ton thu'dng d glai doan tien trien (AGC). Vi tri ton thudng vung hang mon vi va hang vj - goc BCN 50,6% (65/127). Chiem da so \ei ung thii bieu mo tuyen cd biet hoa 85,1%
(108/127), biet hda mii'c dp trung binh: 52,8%, ung till/ dang TB nhan 7,9% (10/127). Ti I? nhilm H.pylori tren Bn UTDD 1^ 54,3% (69/127). Ba mu'di tam chung H. pylori da dudc phan l$p bSng nuoi cay. 100%
(38/38) chiing H. pylori cd mang gene cagA, trong dd cagA ty'p 06ng A chlem 94,7% (36/38), cagA typ phuWng TSy chigm 5,3% (2/38). Tai vi tri khoang 300- bp tren dong (upstream) EPIYA dau tien cua gen cagA, tat ci chOng H. pylon mang cagA typ Dong A deu cd mat do?n 18-bp (84,2%, 32/38) hole 39-bp (10,5%, 4/38). Cac chiing H. pylori mang cagA typ PhUdngTay khong c6 hai dang mkt doan nay. vacA s i la 100%
(38/38). Ty I? yacA m l and m2 la 60,5% va 39,5%.
cagA t/p Oong A cd gen vacA s l / m l la 60,5% (23/38), cagA ti^p Ddng A va cagA phudng Tay cd gen vacA sl/m2 la 34,2% (13/38)va 5,3% (2/38). Khong cd diLing H. pylori ndo mang kieu gen vacA s2/ml hay vacA s2m2 dUdc phat hien.
KSt lu$n; Ti l§ nhilm H. pylori tren benh nhan IJTDD d VN la 54,3%, cagA(+) 100%, typ cagA Dong A chiem 94,7% va vacA s i la 100%, vacAsl/ml la 60,5%, vacAsl/m2 39,5% va su" mat doan 18 bp diiem 84,2% \h mpt d^c tinh dSc trutig cho cac chiing H. pylori phan lap Vi?t Nam
Tiy khoa: cagA, vacA, Helicobacter pylori, ung thu'd? day.
'Benh vl$n Ch^Riy - TP. Ho Chil^lnh
** Binh viin Trung WOng QuSn Doi 108, Ha Ngi Phan bifn khoa hpc:TS Nguyen Canh Binh
S U M M A R Y
ANALYSIS OF CAGA, VACA VIRULENCE FACTORS OF HELICOBACTER PYLORI
I N GASTRIC CANCER Objectives: To determine cagA, vacA vinjlence factors of Helicobacter pylori in gastric cancer
Materials and Methods: The subjects consisted of 127 gastric cancer patients diagnosed by endoscopic observation and confirmed by histopathologicat examination from biopsy specimen. This is a crossing described prospective study and the data were analyze by SPSS 20.0 software.
Results: A total of 127 gastric cancer patients were recruited, comprising of 98 males, 29 females (males/females rario: 3,4) aged from 34-87 years old, mean 63,2years. All patients were diagnosed as advandced gastric cancers, the location of antral and antral incisura angularis of lesser curvature tumors were 50,6%. Gastric differentiated adenocarcinoma was 85,1% (moderately differentiated adenocarcinoma was 52,8%); and signet ring cell carcinoma was 7,9%.
The overall prevalence of H. pylori infection was 54,3%. Thirty eight H. pylori strains were obtained by culture. cagA gene was found In 100% of the isolated strains in which East Asian-type cagA was 94,7% and Western-type cagA was 5,3%. About 300 bp region located upstream of the first cagA EPIYA motif, all strains carrying East Asian-type cagA had 18 bp (84,2%, 32/38) or 39 bp (10,5%, 4/38) deletion. No strains carrying Western-type cagA had these kinds of deletion. vacA s i genotype was found in all strains.
The vacA m l and m2 genotype were found in 60,5%.
and 39,5%. East Asian-type cagA strains were vacA s l / m l (60,5%, 23/38), East Asian-type cagA and Westem-type cagA strains were vacA sl/m2 (34,2%, 15/38), (5,3%, 2/38), no strains carrying s2/ml or s2m2 were found.
Conclusions: Our study found that the prevalence of Helicobacter pylori injection in gasbic cancer patients in Vietnam was 54,3%. The ratio of cagA(+) was 100%, East-Asian type cagA (94,7%), Western type cagA (5,3%) and the ratio of cagA s i was 100%, vacA s l / m l ( 60,5%), vacA sl/m2 (39,5%). The 18-bp deletion type cagA was 84,2%
(32/38), this is a characteristics of H. pylori strains isolated from Vietnam.
Keywords: cagA, vacA, Helicobacter pylori, gastric cancer.
Y HOC VIET NAM THANG 7 - S6 1/2014 I. DAT VAN DE
Ung thu" da day (UTDD) la mpt benh cd ti le mac va tir vo,ng cao tren the gidi, dac biet la cac nu'dc Chau A va cac nu'dc dang phat trien, la nguyen nhan gay tiT vong duYig hang thiT hai do ung thu'. Theo thong ke, trong nam 2002 cd khoang 930.000 tru'dng hdp UTDD du'dc chan doan mdi va tir vong do ung thu' nay la 700.000 ngu'di. Helicobacter pylori W. pylon) la vi khuan Gram am cd dang hinh xoan va song d Idp bleu mo niem mac da day ngu'di. Nhilm H. pylori chiem hdn nii^ dan so tren the gidi va la nguyen nhan chinh gay benh d da day ta trang, nhu" viem da day ta trang, loet da day ta trang, ung thu' bieu mo tuyen da day va lymphoma bao B nguyen phat d da'day^(MALT). Nam 1994, to chifc y te the gidi cho rang H. pylori \h tac nhan gay ung thu" thuoc nhdm I [7].
Benh sinh cua UTDD la qua trinh tac dong qua lai ciia nhieu yeu to, gom: Cac yeu to dpc li/c cua vi khuan, ban chat gien di truyen ciia vat chil va yeu to moi tru'dng
Ngay nay, cac nghien ciru da xac dinh H.
pyiori co nhieu yeu to dpc li/c va cagA, vacA cd vai trd quan trpng trong bieu hien benh. Viet Nam la nu'dc cd ty le nhiem H. pylori va UTDD cao (24,4/100.000 doi vdi nam va 14,6/100.000 doi vdi nuO- Do dd, viec nghien cufu cac yeu to doc life ciia H. pylori giiip hieu ro hdn benh sinh UTDD do nhilm H. pyiori \a can thiet. Vi vay, de tai nghien ciiu nay du'dc thy'c hien nham: /Chao sat cac yiu to dpc iu'c cagA va vacA cua H.
pylori tren benh nhan UTDD
II. Ddl TU'(?NG VA PHU'CTNG PHAP NGHIEN CUU 2.1. Dw tu'cfng nghien cull
Nghien CU\J du'dc thyc hien tu" thang 03/2013 den thang 09/2013 tren 127 BN, du'dc chan doan LfTDD ngoai tam vj, tai Benh vien Trung u'dng Quan ddi (TWQD) 108 - Ha Nol va Benh vien Chd Ray - TP. Ho Chi Minh
III. K f r QUA NGHIEN CU'U 3.1. Dac diem nhom nghien cihi
127BN UTDD: Nhdm BVCR 91 BN, nhdm BVTW/QO-lOB 36BN Trong dd, nam: 77,2% (98/127), nu' 22.8% (29/127), Nam/nu- la 3,4 Tuoi trung binh la 63,2 (34-87tu6i) ^
Bangl:9\\hT\ bo theo nhdm tuoi
2.2. Phi/tfng phap nghien cufu 2.2.1. Tieu chuan chon benh v^ loai trCr Benh nhan chan doan UTDD ngoai tam vi qua noi sol va ket qua mo benh hpc ^
Tiiu chuan loai trir bao gom: BN da phau thuat cat da day, da sir dung cac thuoc tiet trir H. pyiori, hoac cd sir dyng khang sinh, cac thuoc khang tiet acid, trong vdng 2 tuan tru'dc khi tiiam gia nghien ciTu.
2.2.2. Thu thap mau
Tru'dc khi npi soi, tat ca BN du'dc^phdng van theo mau phieu nghien ciru thdng nhat da du'dc thiet ke san. Tien hanh ndi soi DD-TT va sinh thiet 08 mau: 03 mau d hang vj, 02^mau d than vj va 03 mau d khoi u, gom: 01 mau d hang vj vVhoac 01 mau d than vj de nuoi cay tim H.
pylori, 01 mau d hang vi va 01 manh d than vj lam md benh hpc (MBH) va hda mo mien djch (HMDM); 01 mau hang vi la urease test nhanh (CLO test) va 03 mau d u xac dmh MBH va BN du'dc lay 5 ml mau de thyc hien xet nghiem KT khang H. pylori.
2.2.3. I^ut^gphap xic d^nh nhiem H.pytm1 Chan doan nhiem H. pylori dya vao 5 phu'dng phap sau: xet nghiSm tim KT khang H.
pyiori tronq huyet thanh (sir dyng EUSA E Plate kit ciia Eiken Chemical Co., Tokyo, Nhat Ban), MBH, HMMD (sir dung KT, cac hda chat ciia Dako, Dan Mach), Urease test nhanh (CLO test) va nuoi cay. )<ac djnh nhi^m H. pyiori Vini ket qua nudi cay ii. pyiori du'dng tinh hoac neu nuoi cay cho ket qua am ti'nh nhu'ng cd it nhat 2 trong 4 xet nghiemi cdn lai cho ket qua du'dng tinh va khdng nhiem H. pyiori khi ca 4 hoac 5 xet nghiem tren cho ket qua am tinh.
2.2.4. Phwangphip chan doan MBH Chan doan UTDD bang MBH du'dc tai khoa Giai phau benh 1^ ciia benh vien TWQD 108 va benh vien Chd Ray, thed xep loai md benh hoc ciia WHO nam 2002.
Tuoi Difdn 40 tuoi
40-49 tuoi 50-59 tuoi 60-69 tuoi Tren 70 tuoi
Tong
So lu'dng 5 12 33 41 41 127
TV le % 3,9%
9,4%
26,0%
28,3%
32,3%
100°/.
y HQC VlgT NAM THANG 7 - SO 1/2014
Bang 2: : Vl tri u tronq da day Vj tri u tren nol soi
Hang mon vj Goc BCN HV-GBCN Than vi Toan bo da day
long
So lu'ong 49 32 16 27 3 127
Ty le »/o 38,6%
25,2%
12,6%
21,3%
2,4%
100%
a 3: Cac typ md benii iigc Md binh hoc Carcinoma tuyen biet fioa tot Carcinoma tuy§n biet lioa trung binti Carcinoma tuyen tuyen biet hoa i<em Cardnoma tuyen nhay
Carcinoma da day dang TB nhan Carcinoma ong tuyen nhu Carcinoma TB TK noi tiet Lymphoma dong TB B idn
Tong cong
So lu'ong 9 67 32 4 10 1 1 3 127
Ty le »/o 7.1 52.8 25.2 3.1 7.9 0,8 0,8 2.4 100.0
Bang4:X\ le nhiem H. pylori X^t nghiem Nuoi cay
Huyet thanh chan doan H.pylort Urease test
Mo benh hoc Hoa mo mien dich Nhiem H.pylorl
Tyl?
38/127 103/127 56/127 52/127 54/127 69/127
»/o 29,9%
81,1%
44,1%
40,9%
42,5%
54,3%
P P<0,0001 P<0,0001 P=0,21 P<0,05 P=0,11
Bang 5; Ty le va phan bo cac typ cagA, vacA cua h Kllu gene cagA, vacA s/m
cagA typ Donq A cagA typ phu'dng Tay vacA si (n,%) vaeAs2{n,%) vacA sl/ml (n,%) vacAsl/m2{n,°h')
. pylori Nhom benh nhan Ha N6I (n=13)
12 1 13 0 10
3
Tp. HCM(n=25) 24
1 25
0 13 12
T6ng (n, % ) 36(94,7%)
2(5,3%) 38 (100%)
0 23(60,5%) 15(39,5%) Bing 6: Qic typ mat doan cua Pre-EPIYA
Typ mat doan 18-bp deletion 39-bp deletion No deletion Tong (O/o)
CagA dong A (n) 32
4 0 36 (94,7%)
CagA phu'dng Tay (n) 0 0 2 2 (5,3%)
n, % 32I84j2%)
4(10,5%J 2(5,3%
38 (100%)
Y Hpc VIET NAM THANG 7 - SO 1/2014 IV. BAN LUAN
4.1. Gidi va tuol
UTDD CO the gap d bat ky lu'a_ tuol nao, nhu'ng theo nghien cu'u cua nhieu tac gia cho thay UTDD rat it gap d lira tuol thieu nien va ti ie UTDD tang dan sau tuoi 40. Theo nghjen cu'u cua Chung toi, tuol trung binh ia 63,2 (tuoi thap nhat la 34 tuoi, tuoi cao nhat la 87 tuoi) va f le BN tren 60 tuoi chiem 60,6% (xem bang 1), cung tu'dng td nhit die tac gla nu'dc ngoai d Nhat ia 60,6 tuoi va d BiJc la 64,4, nhuiig cao hdn cac nghien ciiu ciia cac tac gia trong nu'dc nhu': Mai Hong Bang (2006) ia 52,8 tua, Tran Van Hdp (2007) ia 54,7 tuoi [2],[6]. Ve gidi tinh, tan suat mac UTDD d nam gidi cao hdn d nff gidi va ti ie nav; l<hac nhau giuS cac nu'dc va cac i<hu vi/c, nghien ciTu ciia chiing toi ti le nam/nu' la: 3,4, ti ie nay tu'dng tu' ntiit cac tac gia trong nu'dc tru'dc day.
4.2. Vi tri u
LTTDD CO the d bat id vj tri nao trong da day nhutig cd tan suat khac nhau, cac nu'dc phat trien v| tri viing tam v| chiem da so [4], cac nghien cirti cbng cho thay rang nhDlig viing cd ti le nhiem H. pylori caa thi ti le UT viing HMV cao. 0 Viet Nam, cac nghien culj tru'dc day cung cho thay vj tri u chlem da so ia viing hang mon vi > 61% (f4ai Hong Bang (2006) la 70,4%, Do Oirc Van (1992) ia 62%, Trjng Hong Son (1997) ia 61,2%. Nghien ciiu cita Chung toi da Ioal trir vj tri u iS viing lam vj va u d vi tri hang mon vi chiem ia 38,6%
(49/127), liang m6n vi-gdc BCN 12,6% (16/127), gdc BCN 25,2% (32/127), than vi 21,3%
(27/127), toan bo da day 2,4% (3/127).
4.3. Cac typ nio bSnh hoc u
Theo phan ioai cua WHO, 127 ca UTDD ciia Chung toi chiem da so la ung thu' bieu mo tuyen cd biet hda 85,1% (108/127) trong dd chlem phan Idn ia ioal cd mu'c do biet hda trung binh 52,8% (nhdm biet hda cao: 7,1% (9/127), nhdm biet hda trung binh: 52,8% (67/127), nhdm biet hda kem 25,2%; ung thu' tuyen nhay 3,1%
(4/127),; ung ttiit tuyen nhu 0,8% (1/127), ung thtf dang TB nhan 7,9% (10/127), ung thtf TB than kinh noi tiet 0,8% (1/127); Lymphoma ddng TB idn 2,4% (3/127). Ket qua nay cung ttfdng ttf nhtf cac tac gia trong ntfdc trtfde day [2],[6].
4.4. Tl ie nhiem H. pylori
Ti le nhiem H. pylori trong UTDD ciia chiing toi ia 54,3% Ifi'iim), ti le nhiem nay ttfdng ttf nhtf trong nghien cirti cua Tran Thien Trung (2011) la 57,7% (41/71) nhtfng thap hdn cua tac gia Tran Van Hdp (2007) 66,3% [6], va ti le nay cung thap hdn ti ie nhiem H. pylori ttonq dan so Viet Nam la 66%, dieu nay cung cd the li giai la do: 1- UTDD trong nhdm nghien ctfu ciia chiing
toi deu is giai doan mupn, tdn thtfdng idn do do khong con vimg niem mac ianh de vi khuan sinh song; hai la qua trinh hinh thanh UT keo dai nhieu nam, benh nhan cd trieu chimg cua benh ly da day va da dtfdc dieu trj trtfde dd va vo tmh da diet ludn vi khuan H. pylori, vi vay de danh gia ri le nhilm H. pylori trong dan so HT chan doan H. pylori thtfdng dtfdc stf dung vi cd dp nhay cao, cung phii hdp vdi ket qua HT chan doan H. pylori trong nghien ciru Chung toi ia 81,1% (103/127) (theo bang 4)
4.5. Ti le cagA, vacA
Gen cagA nSm d cuoi ciia doan DNA cd trpng itfdng 40-kb. Ooan DNA nay dtfdc gpi ia tieu dao sinh benh eag icag PAT - cag pathogenicity island). Cag PAI chtfa 31 gen, trong dd cd 6 gen dtfdc xem la cd chtfc nang ma hoa cac thanh phan ciia he thong bal tiet vi khuan typ IV (Type IV secrection system - TFSS). Sau khi vi khuan H.
pylori bam vao NMDD, cagA ciia H. pylori Slide bdm trtfc tiep vao trong te bao thong qua liS thong bal tiet typ IV. Ben trong te bao bleu mo da day, cagA se theo con dtfdng phosphoryl ho^
tyrosine va cudi cimg ia gay hien ttfdng chet te bao theo chtfdng trinh (apoptopsis), gia tSng qua trtnh sao chep DNA dan den gia tang cd hoi dot bien gen va bat thtfdng tang sinh te bao.
Nhu'ng hien ttfdng nay chtfng td vai tro gay ung thtf ciia CagA trong benh sinh UTDD. cagA cd 2 phan typ: cagA typ phtfdng Tay (Western) va cagA typ Dong A (East Asian).
Mpt yeu to dpc iu'c ne'e ciia H. pylott ia dpc to gay khong bao vacA, gen vacA hien dien d tat ca cac chiing H. pylori. Gen vacA cd trpng itfdng phan tir S8-kDa, dpc to nay se tac dpng ien te bao bieu md thdng qua hien ttfdng i<hdng bao hda bao ttfdng va dan den hien ttfdng chet te bao chtfdng trinh, pha hiiy cau triic bd khung te bao va iam bien ddl cac d^p u'ng mien djch.
Trong moi gen vacA, cd hai viing khac nhau dd ia: viing tin hieu s (signal region - si hoac s2) va viing giii'a m (middle region ml hoac mZ).
Nhieu nghien ctfu trtfde day cung cho thay, da so cac Chung H. pylori ca kieu gen si, sil ml thi cd dpc ltfc eao hdn sl/m2, nhtfng chiing H.pylorica s2/m2 khdng cd ddc ltfc nay va s2/ml chlem d i?
rat thap va rat hiem iien quan den benh [3].
Trong nghien ctfu ciia chung tdi tren 127 BN UTDD, phan lap dtfdc 38 chimg H. pylori trong dd vacA si ia 100% (38/38), s2=ts, sl/ml=
60,5% (23/38), Ji/m2=39,5% (15/38), ket qua nay cung ttfdng ttf nhtf Tran Thien Trung (2011),
Y HOC VlgT NAM T H A N G 7 - SO 1/2014
Si chiem 100%, sl/ml=6'i,6Vii (42/66), sl/m2=36 (24/66), nhtfng cd stf khac biet giii^ 2 nhdm HCM va HN: nhdm HN j V ' . ' c h i e m 7 7 % (10/13), trong khi dd nhdm HCM sl/ml chiem 52% (13/25) (bSng 6).
Ttf 38 Chung H. pylori tren BN UTDD trong nghien ctfu ciia Chung toi cho thay ia H. pylori ca yeu to dpc iu'c cao nhtf; cagA ( + ) (100%), cagA typ Ddng A (94,7%), vacA si (100%), vacA j V m ; ( 6 0 , 5 % ) , i'ac4si//77^(39,5%)
M^c dil trong nghien ciTU cua chung tdi cd mau con nhd (n=127) nhtfng cung cho thay rang qua trinh b^nh sinh LTTDD ia stf tac ddng phtfc t^p ciia nhieu yeu t d nhtf yeu t d vat chii, yeu t d moi tnrdng, che dp an va yeu t d ddc itfc vi khuan, thi ddc itfc vi khuan ia mpt yeu t d khdi dBu quan trpng trong chuoi benh sinh ciia UTDD.
4 . 6 . M3't doan ( 1 8 - b p deletion, 3 9 - b p deletion) t r e n dong cua EPZYA motif thu' nhSt ciia gen cagA ( P r e - E P I Y A )
Cd 3 kieu mat doan phi'a tren dong (upstream) ciia gen cagA tai vj t r i khoang 300-bp tren dong ciia viing lap iai Glu-Pro-Iie-Tyr-Ala (EPIYA) thtf nhat, da dtfdc xac djnh ia typ mat doan 39-bp, typ mat doan 18-bp va typ khong mat doan. Cac nghien cirtJ trtfde day (du' iieu ciia GenBank) cho thay typ mat doan 39-bp tlii hien dien d cac chiing H. pylori is vimg Ddng A nhtfng hau nhtf khdng cd d cac ntfdc phtfdng Tay, con typ mat doan 18-bp chi thay d cac chiing chau A, s^r phan bo nay •An chtfa ro rang vi sd Itfdng mau qua nhd, theo genbank (table 6), Viet Nam cd 4 chiing H. pylori 6itds phan lap (sequences), cd V4 (75%) typ mat doan 18-b'p va 'A (25%) t^p mat doan 39-bp, ngoai ra eon cd HongKong va Thai Lan cung ed mat doan 18-bp, nhtfng chiem ty ie thap. Ttf d d , cung cho thay rang typ mat doan 18-bp ia mdt diem mdi cho stf phat hien chung H. pytoritten ngtfdi Viet Nam. Trong nghien cifti eiia chiing tdi, typ cagA Bdng A deu CO mat doan 9 4 , 7 % (36/38), typ cagA phtfdng tay khdng cd mat doan 5,3% (2/38), typ mat doan 18-bp chiem 8 4 , 2 % (32/38), typ mat doan 39-bp 10,5%, khdng mat do?n 5,3% (2/38). Kgt
<\ui nay cung ttfdng ttf nhtf tac gia Uehida T va Nguyen Lam Tung (2009) khi phan tich cae Chung H. pylori tren viem da day d ngtfdi Viet Nam, typ mat doan 18-bp chlem 7 7 % (80/103)
(ve dja dtf HCM 8 0 % , HN 76%) va typ mat doan 39-bp 13% (13/103). Oleu nay cho ta thay stf mat doan nay mang tinh dac trtfhg cho cac chiing H. pylori is Viet Nam i<hdng? Tuy nhien, cho den nay v l n chtfa ed nghien ctfu nao tim thay stf iien quan giii:a bieu hien iam sang va stf mat doan nay va can cd nhieu nghien ciru hdn de tim sir lien quan khac biet nay vdi cac Chung H.
pytori\iiac va stf bieu hien benh.
V.KfrLU^N
Ti le n h l l m H. pytoritten benh nhan UTDD d VN ia 54,3%, cagA (-1) 100%, typ cagA Ddng A Chlem 94,7% va vacA si ia 100%, vacA sl/ml la 60,5%, vacA sl/m2 3 9 , 5 % va stf mat doan 18- b.p chiem 84,2% la mpt dac tinli dac trtfrig cho cac chiing H. pyloriphan lap d Viet Nam
T A I UEU T H A M KHAO
1 . Tran Ng9c Anh (2006). "Nghien ciili cac type ciia Helicobacter pylori v^ stf bleu 16 Protein P53 d benh nhan ung thtf da day". LuSn an Tien sT Y hgc. Trtfdng Oai hgc Y Ha Ngi.
2. Mai HBng Bang (2006). "Oic diem 13m sang, hinh anh ngi soi va mo benh ligc ciia ung thtf da day". Y hgc thtfc hanh, so 2, trang: 87-89.
3. Basso 0., Zambon C F , et al (2008), "Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms". Gastroenterology 135, pp:91-99.
4. Crew K.D., Neugut A . I . (2006), "Epidemiology of gastric cancer", World Journal of Gastroenterology, 12(3), pp. 354-362.
5. Ho Oang Quy Dung, Tran Oinh Tri, Nguyin Lam Timg, Trjnh Tuan Dung, Mai Hong Bang, Tomohisa Uehida, Toshio Fujioka (2012).
"Nghien ctfu cac yeu to doc itfc cagA, vacA cua Heliobacter pylori va ton thtfdng mo benh hgc viem da day man tfnh", Y hgc Thanh pho Ho Chl Minh, 16, tr. 159-165.
6. Tran Van H?(p va Le Trung Thg (2007). "Ty 1?
nhilm Helicobacter pylori d benh nhan ung thtf da day tai Ha Ngi va khu vtfc nong thon ngoai Ha Ngi". if hoc TP'.CM, tap 11, so 3, trang: 75-79.
7. lARC monographs on the evaluation of carcinogenic risks to humans. Schistosomes, Liver Flukes and Helicobacter pyiori (1994). Lyon:
France; International Agency for Research on Cancer, vol.61, p.p: 177-240
