Roberto Herrera-Goepfert

Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis

Background and 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.

Epstein-Barr virus associated gastric carcinoma: Epidemiological and clinicopathological features

In this paper, the roles of Epstein‐Barr virus (EBV) in gastric carcinogenesis are discussed, reviewing mainly epidemiological and clinicopathological studies. About 10% of gastric carcinomas harbor clonal EBV. LMP1, an important EBV oncoprotein, is only rarely expressed in EBV‐associated gastric carcinoma (EBV‐GC) while EBV‐encoded small RNA is expressed in almost every EBV‐GC cell, suggesting its importance for developing and maintaining this carcinoma. In addition, the hypermethylation‐driven suppressor gene downregulation, frequently observed in EBV‐GC, appears to give a selective advantage for carcinoma cells. EBV reactivation is suspected to precede EBV‐GC development since antibodies against EBV‐related antigens, including EBV capsid antigen (VCA), are elevated in prediagnostic sera. Interestingly, the average anti‐VCA immunoglobulin G antibody titer in EBV‐GC patients was significantly higher among men than among women, whereas EBV‐negative GC cases did not show such a sex difference. A higher frequency of human leucocyte antigen‐DR11 in EBV‐GCs suggests that major histocompatibility complex‐restricted EBV nuclear antigen 1 epitope recognition may enhance EBV reactivation. EBV infection of gastric cells by lymphocytes with reactivated EBV is suspected to be the first step of EBV‐GC development. Male predominance of EBV‐GC suggests the involvement of lifestyles and occupational factors common among men. The predominance of EBV with XhoI+ and BamHI type i polymorphisms in EBV‐GC in Latin America suggests a possibility of some EBV oncogene expressions being affected by EBV polymorphism. The lack of such predominance in Asian countries, however, indicates an interaction between EBV polymorphism and the host response. In conclusion, further studies are necessary to examine the interaction between EBV infection, its polymorphisms, environmental factors, and genetic backgrounds. (Cancer Sci 2008; 99: 195 –201)

Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis

Background:Meta-analyses of the published literature indicate that about 9% of gastric cancers contain Epstein-Barr virus (EBV), with consistent and significant differences by sex and anatomic subsite. This study aimed to identify additional determinants of EBV positivity and their joint effects.Methods:From 15 international populations with consistent laboratory testing for EBV, we pooled individual-level data for 5081 gastric cancer cases including information on age, sex, subsite, histologic type, diagnostic stage, geographic region, and period of diagnosis. First, we combined population-specific EBV prevalence estimates using random effects meta-analysis. We then aggregated individual-level data to estimate odds ratios of EBV positivity in relation to all variables, accounting for within-population clustering.Results:In unadjusted analyses, EBV positivity was significantly higher in males, young subjects, non-antral subsites, diffuse-type histology, and in studies from the Americas. Multivariable analyses confirmed significant associations with histology and region. Sex interacted with age (P=0.003) and subsite (P=0.002) such that male predominance decreased with age for both subsites. The positivity of EBV was not significantly associated with either stage or time period.Conclusion:Aggregating individual-level data provides additional information over meta-analyses. Distinguishing histologic and geographic features as well as interactions among age, sex, and subsite further support classification of EBV-associated gastric cancer as a distinct aetiologic entity.

Case–case comparison of smoking and alcohol risk associations with Epstein–Barr virus-positive gastric cancer

Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein–Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, nonantral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual‐level data on 2,648 gastric cancer patients, including 184 (7%) with EBV‐positive cancers; all studies had information on cigarette use (64% smokers) and nine had data on alcohol (57% drinkers). We compared patients with EBV‐positive and EBV‐negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within‐population clustering, multilevel logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal‐type), anatomic subsite (61% noncardia) and year of diagnosis (1983–2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 [95% confidence interval (CI) 1.6–3.2]. The OR was attenuated to 1.5 (95% CI 1.01–2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR 1.4; adjusted OR 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV‐positive than EBV‐negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV‐positive cancer further implicate the virus as a cofactor in gastric carcinogenesis.

Dietary folate and vitamin B12 intake before diagnosis decreases gastric cancer mortality risk among susceptible MTHFR 677TT carriers.

OBJECTIVE To assess gastric cancer survival in relation to dietary intake of methyl donors and the methylenetetrahydrofolate reductase 677C>T (MTHFR 677C>T) polymorphism. METHODS A prospective cohort of 257 incidental, histologically confirmed gastric cancer cases was assembled in January 2004 and followed until June 2006. Patients were recruited from the main oncology and/or gastroenterology units in Mexico City and were queried regarding their sociodemographic information, clinical history, and dietary habits 3 y before the onset of their symptoms. The intake of methyl donors was estimated with a food-frequency questionnaire and the MTHFR 677C>T polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism analysis. Coxs multivariate regression models were used to estimate the mortality risk of gastric cancer. RESULTS MTHFR 677TT carriers with low folate and vitamin B12 intakes had the lowest survival rate in cases of gastric cancer. High intakes of folate and vitamin B12 before diagnosis was associated with decreased gastric cancer mortality risk in susceptible MTHFR 677TT carriers (mortality risk for folate 0.14, 95% confidence interval 0.04-0.46, P for trend=0.001; mortality risk for vitamin B12 0.23, 95% confidence interval 0.08-0.66, P for trend=0.008). CONCLUSION Folate and related B vitamins may be used as an intervention strategy to improve the survival outcome of gastric cancer.

High-risk human papillomavirus in mammary gland carcinomas and non-neoplastic tissues of Mexican women: No evidence supporting a cause and effect relationship

Human papillomavirus (HPV) has been implicated in breast carcinogenesis. Consecutive and non-selected mastectomy specimens from Mexican patients harboring breast carcinomas were sampled in order to look for the presence of HPV DNA. HPV-16 was detected in 6 (10%) of 60 breast carcinomas. Two of these also had HPV genome in adjacent non-neoplastic mammary-tissues. Seven cases had HPV DNA only in non-neoplastic tissue specimens. HPV DNA was also detected in 4 (25%) of 10 tumor-bed specimens without residual neoplastic lesions that were obtained from patients who underwent neoadjuvant chemotherapy or neoadjuvant chemotherapy/radiotherapy. HPV-positive tumors tended to be smaller in size, than HPV-negative tumors (p=0.047). Histological distributions of HPV-positive and -negative cases showed no significant difference. Although all the HPV-16 DNA were found integrated, its low viral load rendered it difficult to incriminate this virus in breast carcinogenesis. However, the possibility that HPV infection occurred during carcinoma development cannot be ruled out.

Molecular Characterization of the Human Stomach Microbiota in Gastric Cancer Patients

Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in two different sets of gastric cancer patients, and compared them with microbial profiles in other body sites. Paired non-malignant and tumor tissues were sampled from 160 gastric cancer patients with 80 from China and 80 from Mexico. The 16S rRNA gene V3–V4 region was sequenced using MiSeq platform for taxonomic profiles. PICRUSt was used to predict functional profiles. Human Microbiome Project was used for comparison. We showed that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51 and 24%, respectively), followed by oral-associated bacteria. Taxonomic (phylum-level) profiles of stomach microbiota resembled oral microbiota, especially when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic sites, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. Our study showed that Hp is the dominant member of the non-malignant gastric tissue microbiota in many gastric cancer patients. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications.

Prediction of the recurrence probability in patients with parotid gland cancer

Results One-hundred and twenty seven patients were included (64 male and 63 female). Mean age was 53 years. Mucoepidermoid carcinoma was found in 34.6%, adenoid cystic 15.7%, adenocarcinoma 14.3% and acinic cell carcinoma 9.4%. Median disease-free survival was 8.3 years (95% CI 4.3–12.2). Logistic regression analysis confirmed that T classification, facial nerve palsy, differentiation grade, age and surgical margins as factors associated to recurrence (p < 0.00001). Using this model, we defined three postoperative risk groups: high, intermediate and low risk with recurrence frequency of 71.4%, 43.1% and 8.8%, respectively (p = 0.0001). Five-year disease-free survival for these groups were 18.7%, 53.9% and 99.9%, respectively (p = 0.00001). Conclusion Our study identifies several significant prognostic factors. Consequently, a prognostic score categorization is proposed, which allows a straightforward calculation of the recurrence risk for a given case, to define therapeutic strategies, for counseling of patient and to design future trials. from 24th Annual Meeting of the National Cancer Institute of Mexico Mexico City, Mexico. 14–17 February 2007