title: Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis.
abstract: OBJECTIVE
  About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors.
  
  
  METHODS
  We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity.
  
  
  RESULTS
  During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4).
  
  
  CONCLUSIONS
  Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, , Rockville, Maryland, USA.
authors.forename: M Constanza
authors.initials: MC
authors.lastname: Camargo
authors.forename: Woo-Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Chiaravalli
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.forename: Alejandro H
authors.initials: AH
authors.lastname: Corvalan
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Roberto
authors.initials: R
authors.lastname: Herrera-Goepfert
authors.forename: Fernando
authors.initials: F
authors.lastname: Meneses-Gonzalez
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kijima
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liao
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Gonzalez
authors.forename: Yashushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Chihaya
authors.initials: C
authors.lastname: Koriyama
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Suminori
authors.initials: S
authors.lastname: Akiba
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gulley
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Charles S
authors.initials: CS
authors.lastname: Rabkin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020031:Epstein-Barr Virus Infections / Q000401:mortality* / Q000821:virology; D005260:Female; D005500:Follow-Up Studies; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000401:mortality* / Q000821:virology*; D015996:Survival Rate; D055815:Young Adult