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1.  A Multiplex Panel of Plasma Markers of Immunity and Inflammation in Classical Kaposi Sarcoma 
The Journal of Infectious Diseases  2014;211(2):226-229.
Kaposi sarcoma (KS) risk is affected by perturbed immunity. Herein, we compared plasma from 15 human immunodeficiency virus (HIV)–negative classic KS cases to plasma from 29 matched controls, using a multiplex panel of immunity markers. Of 70 markers, CXCL10 (IP-10), sIL-1RII, sIL-2RA, and CCL3 (MIP-1A) were strongly and significantly associated with KS, after adjustment for age and smoking status. These and previous observations are consistent with a tumor-promoting role for these cytokines, particularly CXCL10, but the small sample size and case-control design preclude firm conclusions on KS risk or pathogenesis. Larger, well-designed prospective studies are needed to better assess the association of these markers with KS.
PMCID: PMC4334829  PMID: 25149762
classical Kaposi sarcoma; IP-10; sIL-1RII; human herpesvirus 8
2.  Risk of Breast Cancer with CXCR4-using HIV Defined by V3-Loop Sequencing  
Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures.
A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIVgp120-V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencing-based HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [False-Positive-Rate (FPR 3.5) and 2% X4 cutoff], and lower stringency DS (FPR 5.75, 15% X4 cut-off). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (κ) statistics. Case-control comparisons used exact P-values and conditional logistic regression.
In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P=0.06, odds ratio 0.14, confidence interval 0.003-1.03). Smaller case-control prevalence differences were found with high-stringency DS (21% vs 36%, P=0.32), lower-stringency DS (16% vs 35%, P=0.18), and phenotyping (11% vs 31%, P=0.10). HIV-X4-tropism concordance was best between PS and lower-stringency DS (93%, κ=0.83). Other pairwise concordances were 82%-92% (κ=0.56-0.81). Concordance was similar among cases and controls.
HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency deep sequencing and was significantly associated with lower odds of breast cancer.
PMCID: PMC4262599  PMID: 25321183
Chemokine receptors; HIV; AIDS; breast cancer; parallel sequencing; women
3.  Height, Weight, and Body Mass Index Associations with Gastric Cancer Subsites 
Although excess body weight has been associated with cancers of the gastric cardia, relationships with gastric cancer at other anatomic subsites are not well defined. Furthermore, subsite-specific associations with attained height have not been fully assessed.
In 1995–1996, 483,700 Whites enrolling in the multi-state NIH-AARP Diet and Health Study self-reported height and weight. Gastric cancers occurring through December 31, 2006 were ascertained from regional population-based registries. We used Cox regression models to estimate cancer hazard ratios (HRs) for sex-specific tertiles of height and weight and for body mass index (BMI) categories of the World Health Organization.
One thousand incident cancers (48% localized to the cardia, 4% fundus, 6% corpus, 3% greater curvature, 6% lesser curvature, 10% antrum, 2% pylorus, 5% overlapping lesion, and 16% unspecified) occurred an average of 5.4 years after enrollment. After controlling for effects of age, sex, education and smoking, we found an inverse association between height and total noncardia cancers (i.e., fundus, corpus, greater and lesser curvatures, antrum, and pylorus), with HRs vs. tertile 1 of 0.65 and 0.71 for tertiles 2 and 3, respectively (p-trend=0.016). Trends were consistent for individual noncardia subsites. In contrast, although weight and BMI were each associated with risk of cardia cancer, neither was associated with total noncardia cancer nor individual subsites.
Noncardia gastric cancer is associated with short stature but not with high body weight nor obesity. The excess risk for shorter adults would be consistent with the known association of chronic H. pylori infection with growth retardation during childhood.
PMCID: PMC4007380  PMID: 24174008
BMI; cardia; gastric cancer; height; noncardia; weight
4.  Circulating t(14;18)-Positive Cells in Healthy Individuals – Association with Age and Sex but not with Smoking 
Leukemia & lymphoma  2013;54(12):2678-2684.
t(14;18)-positive cells can not only be detected in follicular lymphoma (FL) patients but also in healthy individuals (HI). We used epidemiological data and blood samples of the population-based Study of Health in Pomerania (SHIP) to analyze associations of FL risk factors and t(14;18)-positive cells in HI. Buffy coat samples from 4152 study participants were tested by real-time PCR for t(14;18)-positive cells. Out of 3966 evaluable subjects, 1526 were t(14;18)-PCR positive (38.5%, median 3.9 t(14;18)-positive per million nucleated cells, range 0.6 – 9299). In multivariable analyses age and sex but not parameters of smoking exposure were significantly associated with t(14;18)-prevalence (logistic regression, p < 0.001). Multivariable analyses of t(14;18)-frequency showed a positive association with age but not with sex or smoking. These age and sex associations in HI require careful control in future studies of t(14;18) as a potential biomarker of lymphoma risk.
PMCID: PMC4444076  PMID: 23527525
Follicular Lymphoma; t(14;18); Lymphomagenesis; Healthy Individuals
5.  Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis 
Gut  2013;63(2):236-243.
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.
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.
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).
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.
PMCID: PMC4384434  PMID: 23580779
6.  The Problem of Helicobacter pylori Resistance to Antibiotics: A Systematic Review in Latin America 
Latin America has a high prevalence of Helicobacter pylori infection and associated diseases, including gastric cancer. Antibiotic therapy can eradicate the bacterial infection and decrease associated morbidity and mortality. To tailor recommendations for optimal treatments, we summarized published literature and calculated region- and country-specific prevalences of antibiotic resistance.
Searches of PubMed and regional databases for observational studies evaluating H. pylori antibiotic resistance yielded a total of 59 independent studies (56 in adults, 2 in children, and 1 in both groups) published up to October 2013 regarding H. pylori isolates collected between 1988 and 2011. Study-specific prevalences of primary resistance to commonly prescribed antibiotics were summarized using random-effects models. Between-study heterogeneity was assessed by meta-regression. As a sensitivity analysis, we extended our research to studies of patients with prior H. pylori-eradication therapy.
Summary prevalences of antimicrobial primary resistance among adults varied by antibiotic, including 12% for clarithromycin (n = 35 studies), 53% for metronidazole (n = 34), 4% for amoxicillin (n = 28), 6% for tetracycline (n = 20), 3% for furazolidone (n = 6), 15% for fluoroquinolones (n = 5), and 8% for dual clarithromycin and metronidazole (n = 10). Resistance prevalence varied significantly by country, but not by year of sample collection. Analyses including studies of patients with prior therapy yielded similar estimates. Pediatric reports were too few to be summarized by meta-analysis.
Resistance to first-line anti- H. pylori antibiotics is high in Latin American populations. In some countries, the empirical use of clarithromycin without susceptibility testing may not be appropriate. These findings stress the need for appropriate surveillance programs, improved antimicrobial regulations, and increased public awareness.
PMCID: PMC4268863  PMID: 24589670
7.  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, non-antral 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 9 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, multi-level 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 co-factor in gastric carcinogenesis.
PMCID: PMC3961829  PMID: 23904115
Alcohol; EBV; gastric cancer; smoking; pooled-analysis
8.  Influence of reproductive history and exogenous hormone use on prevalence and frequency of circulating t(14;18)-positive cells in a population-based cross-sectional study 
Cancer Causes & Control  2015;26(3):455-465.
The t(14;18) translocation might represent an intermediate step in the pathogenesis of follicular lymphoma (FL), one of the most common subtypes of non-Hodgkin lymphoma. Circulating t(14;18)-positive cells can also be detected in 30–60 % of healthy individuals at low frequencies. Some studies found a negative association between reproductive factors or use of menopausal hormone therapy (MHT) with FL. The objective of this study was to evaluate whether there is an association between number of frequencies, oral contraceptive (OC) use, menopausal status and MHT, and t(14;18) prevalence and frequency in a representative population analysis based on an epidemiologic study in the northeastern part of Germany.
The analysis is based on results of buffy coat samples from 1,981 women of the Study of Health in Pomerania (SHIP-0) and data obtained in standardized face-to-face interviews. For prevalence, odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression. Frequency data were analyzed using negative binomial regression. The multivariable models included age, number of pregnancies, menopausal status (premenopausal, natural, medical/surgical menopause), OC use and MHT as a measure for exogenous hormone exposure use.
We found no association between reproductive history and combined exogenous hormone use on the prevalence of circulating t(14;18)-positive cells. Modeling MHT and OC use separately in a sensitivity analysis, the MHT parameter yielded statistical significance [OR 1.37 (95 % CI 1.04;1.81)]. t(14;18) frequency was associated with use of OC [incidence rate ratio (IRR) for ever use 3.18 (95 % CI 1.54;6.54)], current use [IRR 3.86 (1.56;9.54)], >10 years use [IRR 3.93 (1.67;9.23)] and MHT [restricted to postmenopausal women; IRR 2.63 (95 % CI 1.01;6.85)] in bivariate age-adjusted analyses. In the multivariable model, medical/surgical menopause [IRR 2.46 (1.11;5.44)] and the category ever use of OC and MHT were statistically significant [IRR 2.41 (1.09;5.33)].
Exogenous hormone use might be a risk factor for t(14;18) frequency rather than for t(14;18) prevalence. Further research on healthy individuals carrying a t(14;18) translocation and possible risk factors for malignant lymphoma is necessary to determine the additional molecular or immunological events that have to occur to develop FL.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-015-0525-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4331597  PMID: 25634026
t(14;18) translocation; Healthy individuals; Reproductive history; Exogenous hormone use
9.  Prevalence and frequency of circulating t(14;18)-MBR translocation carrying cells in healthy individuals 
The t(14;18) translocation is a common genetic aberration that can be seen as an early step in pathogenesis of follicular lymphoma (FL). The significance of low level circulating t(14;18)-positive cells in healthy individuals as clonal lymphoma precursors or indicators of risk is still unclear. We determined the age dependent prevalence and frequency of BCL2/IgH rearrangements in 715 healthy individuals ranging from newborns to octo- and nonagenarians. These results were compared with number of circulating t(14;18)-positive cells in 108 FL patients at initial presentation. The overall prevalence of BCL2/IgH junctions in this large sample was 46% (327/715). However, there was a striking dependence upon age. Specifically, among individuals up to 10 years old, none had detectable circulating t(14;18)-positive cells. In the age groups representing 10–50 years old, we found a steady elevation in the prevalence of BCL2/IgH junctions up to a prevalence of 66%. Further increases of the prevalence in individuals older than 50 years were not seen. The mean frequency of BCL2/IgH junctions in healthy individuals ≥40 years (18–26 × 10−6) was significantly higher than in younger subjects (7–9 × 10−6). Four percent (31/715) of individuals carried more than one t(14;18)-positive cell per 25,000 peripheral blood mononuclear cells (PBMNCs). In comparison, 108 stage III/IV FL patients had a median number of circulating t(14;18)-positive malignant FL cells of about 9200/1 million PBMNCs (range 7–1,000,000). These findings will further improve the understanding of the relevance of t(14;18)-positive cells in healthy individuals as a risk marker toward the development into lymphoma precursors.
PMCID: PMC4216731  PMID: 19030176
t(14;18)-translocation; BCL2; quantitative real-time PCR; healthy individuals; follicular lymphoma
10.  Comprehensive molecular characterization of gastric adenocarcinoma 
Bass, Adam J. | Thorsson, Vesteinn | Shmulevich, Ilya | Reynolds, Sheila M. | Miller, Michael | Bernard, Brady | Hinoue, Toshinori | Laird, Peter W. | Curtis, Christina | Shen, Hui | Weisenberger, Daniel J. | Schultz, Nikolaus | Shen, Ronglai | Weinhold, Nils | Kelsen, David P. | Bowlby, Reanne | Chu, Andy | Kasaian, Katayoon | Mungall, Andrew J. | Robertson, A. Gordon | Sipahimalani, Payal | Cherniack, Andrew | Getz, Gad | Liu, Yingchun | Noble, Michael S. | Pedamallu, Chandra | Sougnez, Carrie | Taylor-Weiner, Amaro | Akbani, Rehan | Lee, Ju-Seog | Liu, Wenbin | Mills, Gordon B. | Yang, Da | Zhang, Wei | Pantazi, Angeliki | Parfenov, Michael | Gulley, Margaret | Piazuelo, M. Blanca | Schneider, Barbara G. | Kim, Jihun | Boussioutas, Alex | Sheth, Margi | Demchok, John A. | Rabkin, Charles S. | Willis, Joseph E. | Ng, Sam | Garman, Katherine | Beer, David G. | Pennathur, Arjun | Raphael, Benjamin J. | Wu, Hsin-Ta | Odze, Robert | Kim, Hark K. | Bowen, Jay | Leraas, Kristen M. | Lichtenberg, Tara M. | Weaver, Stephanie | McLellan, Michael | Wiznerowicz, Maciej | Sakai, Ryo | Getz, Gad | Sougnez, Carrie | Lawrence, Michael S. | Cibulskis, Kristian | Lichtenstein, Lee | Fisher, Sheila | Gabriel, Stacey B. | Lander, Eric S. | Ding, Li | Niu, Beifang | Ally, Adrian | Balasundaram, Miruna | Birol, Inanc | Bowlby, Reanne | Brooks, Denise | Butterfield, Yaron S. N. | Carlsen, Rebecca | Chu, Andy | Chu, Justin | Chuah, Eric | Chun, Hye-Jung E. | Clarke, Amanda | Dhalla, Noreen | Guin, Ranabir | Holt, Robert A. | Jones, Steven J.M. | Kasaian, Katayoon | Lee, Darlene | Li, Haiyan A. | Lim, Emilia | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Moore, Richard A. | Mungall, Andrew J. | Mungall, Karen L. | Nip, Ka Ming | Robertson, A. Gordon | Schein, Jacqueline E. | Sipahimalani, Payal | Tam, Angela | Thiessen, Nina | Beroukhim, Rameen | Carter, Scott L. | Cherniack, Andrew D. | Cho, Juok | Cibulskis, Kristian | DiCara, Daniel | Frazer, Scott | Fisher, Sheila | Gabriel, Stacey B. | Gehlenborg, Nils | Heiman, David I. | Jung, Joonil | Kim, Jaegil | Lander, Eric S. | Lawrence, Michael S. | Lichtenstein, Lee | Lin, Pei | Meyerson, Matthew | Ojesina, Akinyemi I. | Pedamallu, Chandra Sekhar | Saksena, Gordon | Schumacher, Steven E. | Sougnez, Carrie | Stojanov, Petar | Tabak, Barbara | Taylor-Weiner, Amaro | Voet, Doug | Rosenberg, Mara | Zack, Travis I. | Zhang, Hailei | Zou, Lihua | Protopopov, Alexei | Santoso, Netty | Parfenov, Michael | Lee, Semin | Zhang, Jianhua | Mahadeshwar, Harshad S. | Tang, Jiabin | Ren, Xiaojia | Seth, Sahil | Yang, Lixing | Xu, Andrew W. | Song, Xingzhi | Pantazi, Angeliki | Xi, Ruibin | Bristow, Christopher A. | Hadjipanayis, Angela | Seidman, Jonathan | Chin, Lynda | Park, Peter J. | Kucherlapati, Raju | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Kim, Sang-Bae | Lee, Ju-Seog | Lu, Yiling | Mills, Gordon | Laird, Peter W. | Hinoue, Toshinori | Weisenberger, Daniel J. | Bootwalla, Moiz S. | Lai, Phillip H. | Shen, Hui | Triche, Timothy | Van Den Berg, David J. | Baylin, Stephen B. | Herman, James G. | Getz, Gad | Chin, Lynda | Liu, Yingchun | Murray, Bradley A. | Noble, Michael S. | Askoy, B. Arman | Ciriello, Giovanni | Dresdner, Gideon | Gao, Jianjiong | Gross, Benjamin | Jacobsen, Anders | Lee, William | Ramirez, Ricardo | Sander, Chris | Schultz, Nikolaus | Senbabaoglu, Yasin | Sinha, Rileen | Sumer, S. Onur | Sun, Yichao | Weinhold, Nils | Thorsson, Vésteinn | Bernard, Brady | Iype, Lisa | Kramer, Roger W. | Kreisberg, Richard | Miller, Michael | Reynolds, Sheila M. | Rovira, Hector | Tasman, Natalie | Shmulevich, Ilya | Ng, Santa Cruz Sam | Haussler, David | Stuart, Josh M. | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Verhaak, Roeland G.W. | Mills, Gordon B. | Leiserson, Mark D. M. | Raphael, Benjamin J. | Wu, Hsin-Ta | Taylor, Barry S. | Black, Aaron D. | Bowen, Jay | Carney, Julie Ann | Gastier-Foster, Julie M. | Helsel, Carmen | Leraas, Kristen M. | Lichtenberg, Tara M. | McAllister, Cynthia | Ramirez, Nilsa C. | Tabler, Teresa R. | Wise, Lisa | Zmuda, Erik | Penny, Robert | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Curely, Erin | Mallery, David | Morris, Scott | Paulauskis, Joseph | Shelton, Troy | Shelton, Candace | Sherman, Mark | Benz, Christopher | Lee, Jae-Hyuk | Fedosenko, Konstantin | Manikhas, Georgy | Potapova, Olga | Voronina, Olga | Belyaev, Smitry | Dolzhansky, Oleg | Rathmell, W. Kimryn | Brzezinski, Jakub | Ibbs, Matthew | Korski, Konstanty | Kycler, Witold | ŁaŸniak, Radoslaw | Leporowska, Ewa | Mackiewicz, Andrzej | Murawa, Dawid | Murawa, Pawel | Spychała, Arkadiusz | Suchorska, Wiktoria M. | Tatka, Honorata | Teresiak, Marek | Wiznerowicz, Maciej | Abdel-Misih, Raafat | Bennett, Joseph | Brown, Jennifer | Iacocca, Mary | Rabeno, Brenda | Kwon, Sun-Young | Penny, Robert | Gardner, Johanna | Kemkes, Ariane | Mallery, David | Morris, Scott | Shelton, Troy | Shelton, Candace | Curley, Erin | Alexopoulou, Iakovina | Engel, Jay | Bartlett, John | Albert, Monique | Park, Do-Youn | Dhir, Rajiv | Luketich, James | Landreneau, Rodney | Janjigian, Yelena Y. | Kelsen, David P. | Cho, Eunjung | Ladanyi, Marc | Tang, Laura | McCall, Shannon J. | Park, Young S. | Cheong, Jae-Ho | Ajani, Jaffer | Camargo, M. Constanza | Alonso, Shelley | Ayala, Brenda | Jensen, Mark A. | Pihl, Todd | Raman, Rohini | Walton, Jessica | Wan, Yunhu | Demchok, John A. | Eley, Greg | Mills Shaw, Kenna R. | Sheth, Margi | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean Claude | Davidsen, Tanja | Hutter, Carolyn M. | Sofia, Heidi J. | Burton, Robert | Chudamani, Sudha | Liu, Jia
Nature  2014;513(7517):202-209.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
PMCID: PMC4170219  PMID: 25079317
11.  Management of Helicobacter pylori infection in Latin America: A Delphi technique-based consensus 
World Journal of Gastroenterology : WJG  2014;20(31):10969-10983.
AIM: To optimize diagnosis and treatment guidelines for this geographic region, a panel of gastroenterologists, epidemiologists, and basic scientists carried out a structured evaluation of available literature.
METHODS: Relevant questions were distributed among the experts, who generated draft statements for consideration by the entire panel. A modified three-round Delphi technique method was used to reach consensus. Critical input was also obtained from representatives of the concerned medical community. The quality of the evidence and level of recommendation supporting each statement was graded according to United States Preventive Services Task Force criteria.
RESULTS: A group of ten experts was established. The survey included 15 open-ended questions that were distributed among the experts, who assessed the articles associated with each question. The levels of agreement achieved by the panel were 50% in the first round, 73.3% in the second round and 100% in the third round. Main consensus recommendations included: (1) when available, urea breath and stool antigen test (HpSA) should be used for non-invasive diagnosis; (2) detect and eradicate Helicobacter pylori (H. pylori) in all gastroscopy patients to decrease risk of peptic ulcer disease, prevent o retard progression in patients with preneoplastic lesions, and to prevent recurrence in patients treated for gastric cancer; (3) further investigate implementation issues and health outcomes of H. pylori eradication for primary prevention of gastric cancer in high-risk populations; (4) prescribe standard 14-d triple therapy or sequential therapy for first-line treatment; (5) routinely assess eradication success post-treatment in clinical settings; and (6) select second- and third-line therapies according to antibiotic susceptibility testing.
CONCLUSION: These achievable steps toward better region-specific management can be expected to improve clinical health outcomes.
PMCID: PMC4138478  PMID: 25152601
Helicobacter pylori; Consensus development conference; Delphi technique; Latin America
12.  Risk factors for gastric cancer in Latin-America: a meta-analysis 
Cancer causes & control : CCC  2012;24(2):217-231.
Latin America has among the highest gastric cancer incidence rates in the world, for reasons that are still unknown. In order to identify region-specific risk factors for gastric cancer, we conducted a meta-analysis summarizing published literature.
Searches of PubMed and regional databases for relevant studies published up to December 2011 yielded a total of 29 independent case-control studies. We calculated summary odds ratios (OR) for risk factors reported in at least five studies, including socioeconomic status (education), lifestyle habits (smoking and alcohol use), dietary factors (consumption of fruits, total vegetables, green vegetables, chili pepper, total meat, processed meat, red meat, fish and salt) and host genetic variants (IL1B-511T, IL1B-31C, IL1RN*2, TNFA-308A, TP53 codon 72 Arg and GSTM1 null). Study-specific ORs were extracted and summarized using random-effects models.
Chili pepper was the only region-specific factor reported in at least five studies. Consistent with multifactorial pathogenesis, smoking, alcohol use, high consumption of red meat or processed meat, excessive salt intake and carriage of IL1RN*2 were each associated with a moderate increase in gastric cancer risk. Conversely, higher levels of education, fruit consumption, and total vegetable consumption were each associated with a moderately decreased risk. The other exposures were not significantly associated. No prospective study data were identified.
Risk factor associations for gastric cancer in Latin America are based on case-control comparisons that have uncertain reliability, particularly with regard to diet; the specific factors identified and their magnitudes of association are largely similar to those globally recognized. Future studies should emphasize prospective data collection and focus on region-specific exposures that may explain high gastric cancer risk.
PMCID: PMC3961831  PMID: 23224270
epidemiology; gastric cancer; Latin-America; meta-analysis; risk factors
13.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
14.  Increased Levels of Circulating Cytokines with HIV-Related Immunosuppression 
Cytokines may contribute to the severity of CD4 cell depletion with human immunodeficiency virus (HIV) infection, but quantitative relationships are not well defined. Serum and plasma from 181 HIV-infected individuals were tested with Millipore 30-plex Luminex cytokine assays. Within-individual correlations among cytokines were summarized by two-dimensional hierarchical cluster analysis. Associations with age, sex, race, CD4 count, and HIV viral load were determined with linear regression models. Tests for statistical significance were corrected for multiple comparisons, using a false discovery rate of 0.1. African-Americans had significantly higher levels than whites of six cytokines (IL-2, IL-5, IL-7, IL-15, fractalkine, and IFN-γ), and lower levels of MCP-1. Females had higher fractalkine levels than males. Age was not associated with levels of any cytokine. Six cytokines, including the T-helper (Th) type 1 cytokine IL-15, the Th2 cytokines IL-1ra and IL-10, the chemokines fractalkine and MCP-1, and the growth factor G-CSF were each inversely associated with CD4 count; no cytokine was directly associated with CD4 count. Fractalkine was directly associated with HIV viral load, adjusted for CD4 count. Cytokines clustered by primary function (e.g., Th1, Th2, proinflammatory, chemokines, or growth factors) whereas individuals clustered according to cytokine levels (generally high, intermediate, or low) had significantly different CD4 counts [medians (interquartile range) of 60 (17–162), 131 (62–321), and 155 (44–467), respectively; p<0.0001]. CD4 deficiency is associated with generalized increases in cytokines of various functions. Racial differences in cytokine response to HIV infection could contribute to disparities in disease progression.
PMCID: PMC3399552  PMID: 21962239
15.  Sex Hormones, Hormonal Interventions and Gastric Cancer Risk: A Meta-Analysis 
Estrogens may influence gastric cancer risk but published studies are inconclusive. We therefore performed a meta-analysis addressing the associations of gastric cancer in women with menstrual and reproductive factors, and with use of estrogen- and antiestrogen-related therapies. Searches of PubMed up to June, 2011 and review of citations yielded a total of 28 independent studies including at least one exposure of interest. Random effects pooled estimates of relative risk (RR) and corresponding 95% confidence intervals (CI) were calculated for eight exposures reported in at least five studies, including: age at menarche, age at menopause, years of fertility, parity, age at first birth, oral contraceptive use, hormone replacement therapy (HRT), and tamoxifen treatment. Longer years of fertility (RR= 0.74; 95% CI= 0.63 to 0.86) and HRT (RR= 0.77, 95% CI= 0.64 to 0.92) were each associated with decreased gastric cancer risk. Conversely, tamoxifen treatment was associated with increased risk (RR= 1.82, 95% CI= 1.39 to 2.38). The other five exposures were not significantly associated. Our analysis supports the hypothesis that longer exposure to estrogen effects of either ovarian or exogenous origin may decrease risk of gastric cancer. Additional studies are warranted to extend this finding and to identify the underlying mechanisms.
PMCID: PMC3315355  PMID: 22028402
Gastric Cancer; Hormone Therapy; Menstrual Factors; Reproductive Factors; Tamoxifen
16.  Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location 
Gastroenterology  2009;137(3):824-833.
Background & Aims
Epstein-Barr virus (EBV) has been causally associated with cancer; some gastric carcinomas have a monoclonal EBV genome in every cancer cell, indicating that they arose from a single infected progenitor cell. However, the proportion of EBV-positive gastric carcinomas is uncertain and the etiological significance is unknown.
We conducted a meta-analysis of 70 studies including 15,952 cases of gastric cancer assessed by in situ hybridization for EBV-encoded small RNA.
The pooled prevalence estimate of EBV-positivity was 8.7% (95% CI: 7.5, 10.0) overall, with a two-fold difference by sex: 11.1% (95% CI: 8.7, 14.1) of gastric cancer cases in males vs. 5.2% (95% CI: 3.6, 7.4) of cases in females. Tumors arising in the gastric cardia (13.6%) or corpus (13.1%) were more than twice as likely to be EBV-positive as those in the antrum (5.2%; p<0.01 for both comparisons). EBV-prevalence was four times higher (35.1%) for tumors in post-surgical gastric stump/remnants. Over 90% of lymphoepithelioma-like carcinomas were EBV-positive but only 15 studies reported any cases of this type; prevalence did not significantly differ between the more common diffuse (7.6%) and intestinal (9.5%) histologies. EBV-prevalence was similar in cases from Asia (8.3%), Europe (9.2%), and the Americas (9.9%).
EBV-positive gastric cancers greatly differ from other gastric carcinomas based on sex, anatomic subsite, and surgically disrupted anatomy, indicating that it is a distinct etiologic entity. Epidemiologic studies comparing EBV-positive and -negative gastric cancers are warranted to investigate EBV’s role in gastric carcinogenesis.
PMCID: PMC3513767  PMID: 19445939
Epstein-Barr virus; gastric cancer; meta-analysis; prevalence
17.  Circulating cytokine levels, Epstein-Barr viremia and risk of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma 
American Journal of Hematology  2011;86(10):875-878.
Cytokine dysregulation and decontrol of Epstein-Barr virus (EBV) latency by human immunodeficiency virus (HIV) infection are potential mechanisms for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). We therefore assessed circulating blood levels in pre-diagnosis plasma or serum from 63 AIDS-related NHL cases 0.1 – 2.0 (median 1.0) years pre-NHL and 181 controls matched for CD4+ T-cell count. Cytokines were measured by Millipore 30-plex Luminex assays and cell-free EBV DNA detected by polymerase chain reaction (PCR). Correlations in multiplex cytokine levels were summarized by factor analysis. Individual cytokines and their principal factors were analyzed for associations with NHL by conditional logistic regression. Cases had higher levels for 25 of the 30 cytokines. In analyses of cytokine profiles, cases had significantly higher scores for a principal factor primarily reflecting levels of interleukin (IL)-4, IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (four gene products with coordinated transcription in vitro), as well as IL-1alpha. Epstein-Barr viremia was not significantly associated based on 113 evaluable samples without PCR inhibition. We found increases of T-helper type 2 interleukins and generalized elevations of other inflammatory cytokines and growth factors up to two years before AIDS-NHL. Cytokine-mediated hyperstimulation of B-cell proliferation may play a role in AIDS-related lymphomagenesis.
PMCID: PMC3320652  PMID: 22022727
18.  Systemic Cytokine Levels and Subsequent Risk of Gastric Cancer in Chinese Women 
Cancer Science  2011;102(10):1911-1915.
The control of the host cytokine network is known to influence gastric cancer susceptibility; the specific inflammatory responses in gastric carcinogenesis remain unclear.
We prospectively examined the relationships of plasma levels of interleukin (IL)-1β, IL6, IL8 and tumor necrosis factor (TNF)-α to gastric cancer risk within The Shanghai Women’s Health Study. Two controls were matched to each case by age, menopausal status and sample collection parameters. The associations of gastric cancer risk and tertile of cytokine levels were estimated by odds ratios (ORs) and 95 per cent confidence intervals (% CIs) from conditional logistic regression, adjusting for education.
During a median follow-up period of 4 years (range: 0.1–8), 141 women developed gastric cancer and were matched to 282 cancer-free study participants. Elevated levels of plasma IL6 were associated with an increased risk of gastric cancer (Ρtrend=0.04). Risk increased 70% (OR=1.7, 95% CI, 1.0, 3.0) for women in the highest tertile (> 4 pg/mL) of IL-6 compared to those in the lowest tertile (<1.8 pg/mL). The association with IL6 was stronger after 4 years of follow-up (OR=2.6, 95% CI, 1.0, 6.7 for highest vs. lowest tertile) compared to an OR of 1.4 (0.7, 2.9) for those diagnosed within 1–4 years of follow-up. No associations were observed with the other examined pro-inflammatory cytokines, IL1β, IL8 and TNFα.
Systemic plasma IL6 levels may inform long-term gastric cancer risk. This novel finding awaits confirmation in future studies with sequential plasma collection.
PMCID: PMC3349461  PMID: 21740481
cytokine; gastric cancer; prediagnostic
19.  B cell-stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B cell lymphoma 
The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine if elevated serum levels of molecules associated with B cell activation precede the diagnosis of AIDS-associated NHL.
Serum levels of B cell activation-associated molecules, interleukin-6 (IL6), interleukin-10 (IL10), soluble CD23 (sCD23), soluble CD27 (sCD27), soluble CD30 (sCD30), C-reactive protein (CRP), and IgE were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to three time points per subject, 0–5 years prior to AIDS-NHL diagnosis.
Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared to HIV+ controls or to AIDS controls, after adjusting for CD4 T cell number. Elevated serum levels of B cell activation-associated molecules were seen to be associated with the development of systemic (non-CNS) NHL, but not with the development of primary CNS lymphoma.
Levels of certain B cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B cell activation contributes to the development of these hematologic malignancies.
Marked differences in serum levels of several molecules are seen for several years pre-diagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.
PMCID: PMC3132317  PMID: 21527584
lymphoma; B cell; cytokines; AIDS; immune activation
21.  An association between a variation in the PSCA gene and upper gastrointestinal cancer in Caucasians 
Gastroenterology  2010;140(2):435-441.
Background & Aims
An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in Caucasians.
We genotyped 166 relatives of gastric cancer patients, including 43 H pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables.
Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.1–1.9) and non-cardia gastric cancer (OR = 1.9; 95% CI, 1.3– 2.8). The association was strongest for the diffuse histological-type (OR = 3.2; 95% CI, 1.2–10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR = 0.5; 95% CI, 0.3–0.9), esophageal adenocarcinoma (OR = 0.5; 95% CI, 0.3–0.9), and esophageal squamous cell carcinoma (OR = 0.4; 95% CI, 0.2–0.9).
The rs2294008 polymorphism in PSCA increases the risk of non-cardia gastric cancer and its precursors in Caucasians but protects against proximal cancers.
PMCID: PMC3031760  PMID: 21070776
Stomach cancer; esophageal cancer; genetic polymorphisms, cancer genetics
22.  Possible association between a genetic polymorphism at 8q24 and risk of upper gastrointestinal cancer 
Over recent years, genome wide association studies (GWAS) have contributed to our understanding of genetic susceptibility to sporadic cancer. In this study, we assessed the association between upper gastrointestinal cancer risk and four GWAS-identified single nucleotide polymorphisms (SNPs), previously implicated in prostate and colorectal cancer susceptibility. Genotyping for each SNP was performed in two, independent, Caucasian, population-based case-control studies. The first study comprised 290 gastric cancer cases and 374 controls. The second study included 185 non-cardia gastric cancers, 123 cardia cancers, 158 oesophageal cancers, and 209 controls. Odds ratios were computed from logistic models and adjusted for potential confounding variables. An inverse association was observed between the SNP rs1447295, located at 8q24, and gastric cancer risk in the first study population (odds ratio [OR] = 0.63; 95% Confidence Interval [CI], 0.41–0.97). A positive association was observed for the same SNP and oesophageal squamous cell carcinoma in the second study population (OR = 7.43; 95% CI, 1.37–49.98). No significant associations were detected in either study for the three remaining SNPs (rs6983297, rs10505477 and rs719725). Our data represent novel findings on heritable susceptibility to gastric and oesophageal cancer and warrant validation in additional populations.
PMCID: PMC3020097  PMID: 21102338
Gastric cancer; oesophageal cancer; genetic polymorphism; cancer susceptibiility
23.  Divergent trends for gastric cancer incidence by anatomical subsite in US adults 
Gut  2011;60(12):1644-1649.
Background and aim
Age-specific analyses of non-cardia gastric cancer incidence reveal divergent trends among US whites: rates are declining in individuals aged 40 years and older but rising in younger persons. To investigate this heterogeneity further, incidence trends were evaluated by anatomical subsite.
Gastric cancer incidence data for 1976–2007 were obtained from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program and the US Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR). Incidence rates and estimated annual percentage change were calculated by age group (25–39, 40–59 and 60–84 years), race/ethnicity and subsite.
Based on data from the nine oldest SEER registries (covering ~10% of the US population), rates for all non-cardia subsites decreased in whites and blacks, except for corpus cancer, which increased between 1976 and 2007 with estimated annual percentage changes of 1.0% (95% CI 0.1% to 1.9%) for whites and 3.5% (95% CI 1.8% to 5.2%) for blacks. In contrast, rates for all non-cardia subsites including corpus cancer declined among other races. In combined data from NPCR and SEER registries (covering 89% of the US population), corpus cancer significantly increased between 1999 and 2007 among younger and middle-aged whites; in ethnic-specific analyses, rates significantly increased among the same age groups in non-Hispanic whites and were stable among Hispanic whites. Age-specific rates for all subsites declined or were stable in this period among blacks and other races.
Long- and short-term incidence trends for gastric cancers indicate a shifting distribution by anatomical subsite. Corpus cancer may have distinctive aetiology and changing risk factor exposures, warranting further investigation.
PMCID: PMC3202077  PMID: 21613644
24.  Age-Specific Trends in Incidence of Noncardia Gastric Cancer in US Adults 
For the last 50 years, overall age-standardized incidence rates for noncardia gastric cancer have steadily declined in most populations. However, overall rates are summary measures that may obscure important age-specific trends.
To examine effects of age at diagnosis on noncardia gastric cancer incidence trends in the United States.
Design, Setting, and Participants
Descriptive study with age-period-cohort analysis of cancer registration data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, which covers approximately 26% of the US population. From 1977 through 2006, there were 83 225 adults with incident primary gastric cancer, including 39 003 noncardia cases.
Main Outcome Measures
Overall and age-specific incidence rates, adjusted for period and cohort effects using age-period-cohort models. Results were stratified by race, sex, and socioeconomic status.
Overall age-standardized annual incidence per 100 000 population declined during the study period from 5.9 (95% confidence interval [CI], 5.7-6.1) to 4.0 (95% CI, 3.9-4.1) in whites, from 13.7 (95% CI, 12.5-14.9) to 9.5 (95% CI, 9.1-10.0) in blacks, and from 17.8 (95% CI, 16.1-19.4) to 11.7 (95% CI, 11.2-12.1) in other races. Age-specific trends among whites varied significantly between older and younger age groups (P < .001 for interaction by age): incidence per 100 000 declined significantly from 19.8 (95% CI, 19.0-20.6) to 12.8 (95% CI, 12.5-13.1) for ages 60 to 84 years and from 2.6 (95% CI, 2.4-2.8) to 2.0 (95% CI, 1.9-2.1) for ages 40 to 59 years but increased significantly from 0.27 (95% CI, 0.19-0.35) to 0.45 (95% CI, 0.39-0.50) for ages 25 to 39 years. Conversely, rates for all age groups declined or were stable among blacks and other races. Age-period-cohort analysis confirmed a significant increase in whites among younger cohorts born since 1952 (P < .001).
From 1977 through 2006, the incidence rate for noncardia gastric cancer declined among all race and age groups except for whites aged 25 to 39 years, for whom it increased. Additional surveillance and analytical studies are warranted to identify risk factors that may explain this unfavorable trend.
PMCID: PMC3142962  PMID: 20442388
25.  Kaposi Sarcoma-Associated Herpesvirus Serum DNA and Antibodies Not Associated With Subsequent Non-Hodgkin Lymphoma Risk 
Kaposi sarcoma-associated herpes virus (KSHV) infects B-cells and is found in non-Hodgkin lymphoma (NHL) B-cell tumors and could therefore contribute to the occurrence of NHL. We performed a nested case–control study including 155 incident NHL cases and matched noncancer controls. Pre-NHL serum was tested for KSHV DNA and antibodies. Serum KSHV DNA was more common in cases than controls (14% versus 6%, P = 0.03), but after adjustment, the difference was not significant. Epstein-Barr virus serum DNA was similarly unassociated with NHL as were KSHV antibodies. KSHV is not a primary cause of NHL in HIV-infected men who have sex with men.
PMCID: PMC3073851  PMID: 21116187
Kaposi sarcoma-associated herpesvirusp; non-Hodgkin lymphoma; MACS; human herpesvirus 8; DNA; AIDS cancer

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