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È stata condotta unanalisi retrospettiva su 482 pazienti con diagnosi di tumore testa-collo arruolati presso l ospedale Agostino Gemelli di Roma. Lassociazione tra fattori demografici, clinici e comportamentali con la overall survival (OS), il rischio di ricorrenza ed il rischio di un secondo tumore primitivo è stata stimata usando gli Hazard Ratio (HR) e gli intervalli di confidenza al 95% (CIs). La OS considerando tutte le sedi tumorali è stata del 60%, mentre considerando le singole sedi tumorali è risultata del 49.0% per il cavo orale, 54.8% per lorofaringe, 50.0% per lipofaringe e 63.4% per la laringe. Unetà avanzata alla diagnosi (HR = 1.04; 95% CI: 1.02-1.05) ed un avanzato stadio del tumore (HR = 2.00; 95% CI: 1.41-2.84) sono risultati fattori significativamente associati con la OS. Il rischio di ricorrenza è risultato associato con il consumo di alcolici (HR = 1.73; 95% CI: 1.00-2.97). Il rischio di sviluppare un secondo tumore primitivo è risutlato associato con uno stadio avanzato del tumore primario (HR = 2.75; 95% CI: 1.39-5.44) e con laver fumato per più di 40 anni (HR = 3.68; 95% CI: 1.10-12.30). In conclusione abbiamo notato che la OS differisce tra le sedi tumorali del tumore testa-collo. Lo stadio tumorale è risultato essere associato sia con la OS che con il rischo di sviluppare un secondo tumore primitivo. Il consumo di alcol e di tabacco sono risultati essere fattori prognostici, rispettivamente, per la ricorrenza e per linsorgenza di un secondo tumore primitivo.

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture., Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO., Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level., Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO., Funding: German Research Foundation (DFG)., Competing Interests: Declaration of interests MDR reports consulting fees from Roche Diagnostics and Medtronic; leadership or fiduciary role in the European Society of Gastrointestinal Endoscopy (ESGE) and World Endoscopy Organization (WEO). All other authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The association between height and risk of gastric cancer has been studied in several epidemiological studies with contrasting results. The aim of this study is to examine the association between adult height and gastric cancer within a large pooled analysis of case-control studies members of the Stomach cancer Pooling (StoP) Project consortium., Methods: Data from 18 studies members of the StoP consortium were collected and analyzed. A multivariable logistic regression model was used to estimate the study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between 10-cm increase in height and risk of gastric cancer. Age, sex, tobacco smoking, alcohol consumption, social class, geographical area and Helicobacter pylori (H. pylori ) status were included in the regression model. Resulting estimates were then pooled with random-effect model. Analyses were conducted overall and in strata of selected variables., Results: A total of 7562 cases and 19 033 controls were included in the analysis. The pooled OR was 0.96 (95% CI 0.87-1.05). A sensitivity analysis was performed restricting the results to the studies with information on H. pylori status, resulting in an OR of 0.97 (95% CI 0.79-1.20)., Conclusion: Our study does not support a strong and consistent association between adult height and gastric cancer., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Identification of screening tests for the detection of head and neck cancer (HNC) at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating miRNAs for the diagnosis of HNC (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology consortium., Methods: A high-throughput screening phase with 754 miRNAs was performed in plasma samples of 88 cases and 88 controls, followed by a validation phase of the differentially expressed miRNAs, identified in the screening, in samples of 396 cases and 396 controls. Comparison of the fold changes (FC) was carried out using the Wilcoxon rank-sum test and the Dunn multiple comparison test., Results: We identified miR-151-3p (FC = 1.73, P = 0.007) as differentially expressed miRNAs in the screening and validation phase. The miR-151-3p was the only overexpressed miRNA in validation sample of patients with HNC with early stage at diagnosis (FC = 1.81, P = 0.008) and it was confirmed upregulated both in smoker early-stage cases (FC = 3.52, P = 0.024) and in nonsmoker early-stage cases (FC = 1.60, P = 0.025) compared with controls., Conclusions: We identified miR-151-3p as an early marker of HNC. This miRNA was the only upregulated in patients at early stages of the disease, independently of the smoking status., Impact: The prognosis for HNC is still poor. The discovery of a new diagnostic biomarker could lead to an earlier tumor discovery and therefore to an improvement in patient prognosis., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background and Aim: Increased intestinal permeability plays a key role in the pathogenesis of fat deposition in the liver. The aim of our study was to assess whether a single nucleotide polymorphism of protein tyrosine phosphatase non-receptor type 2 (PTPN2) (rs2542151 T→G), involved in intestinal permeability, may be associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM)., Methods and Results: We recruited a prospective cohort of NAFLD subjects and matched controls. Clinical data, PTPN2 genotype and laboratory data were collected for each patient. Results were stratified according to liver histology and diabetes. We enrolled 566 cases and 377 controls. PTPN2 genotype distribution did not significantly differ between patients and controls. In the entire population, patients with PTPN2 rs2542151 T→G (dominant model) have a higher prevalence of diabetes; 345 patients (60.9%) underwent liver biopsy: 198 (57.4%) had steatohepatitis and 75 (21.7%) had advanced fibrosis. At multiple logistic regression analysis PTPN2 rs2542151 T→G was associated with T2DM (OR 2.14, 95% CI 1.04-4.40, P = 0.03). Patients who underwent liver biopsy, rs2542151 T→G of PTPN2 was independently associated with severe steatosis (OR 2.00, 95% CI 1.17-3.43, p = 0.01) and severe fibrosis (OR 2.23, 95% CI 1.06-4.72, P = 0.03)., Conclusion: Our study shows that NAFLD patients with rs2542151 T→G of PTPN2 have a higher severity of fatty liver disease and a higher prevalence of T2DM. These results suggest that individual genetic susceptibility to intestinal permeability could play a role in liver disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Serum amino acid (AA) profiles represent a valuable tool in the metabolic assessment of cancer patients; still, information on the AA pattern in head and neck cancer (HNC) patients is insufficient. The aim of the study was to assess whether serum AA levels were associated with the stage of neoplastic disease and prognosis in primary HNC patients., Methods: Two hundred and two primary HNC patients were included in the study. Thirty-one AAs and derivatives were measured in serum through an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The association between AA concentrations and the stage (advanced versus early) of HNC was estimated using a multivariable logistic regression model. A multivariable Cox regression model was used to evaluate the prognostic significance of each AA., Results: At the multivariable logistic regression analysis, increased levels of alpha-aminobutyric acid, aminoadipic acid, histidine, proline, and tryptophan were associated with a reduced risk of advanced stage HNC, while high levels of beta-alanine, beta-aminobutyric acid, ethanolamine, glycine, isoleucine, 4-hydroxyproline, and phenylalanine were associated with an increased risk of advanced stage HNC. Furthermore, at multivariate analysis, increased levels of alpha-aminobutyric acid were associated with increased overall survival (OS), while high levels of arginine, ethanolamine, glycine, histidine, isoleucine, 4-hydroxyproline, leucine, lysine, 3-methylhistidine, phenylalanine, and serine were associated with decreased OS., Conclusions: Our study suggests that AA levels are associated with the stage of disease and prognosis in patients with HNC. More study is necessary to evaluate if serum AA levels may be considered a hallmark of HNC and prove to be clinically useful markers of disease status and prognosis in HNC patients., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2020 Gabriella Cadoni et al.)

Objective: Few studies report that Mediterranean dietary (MD) pattern has a beneficial role in the progression of non-alcoholic fatty liver disease (NAFLD). Evidence on its potential effect on the onset of disease are, however, scanty. With our study, we evaluated whether MD affects the risk of NAFLD with a large case-control study performed in Italy., Patients and Methods: Three hundred and seventy-one cases of NAFLD and 444 controls were questioned on the demographic data and their dietary habits before diagnosis. Additionally, information about lifestyles and other related diseases, such as hypertension and diabetes mellitus were collected. The MD adherence was assessed using a pre-defined Mediterranean Diet Score (MDS). Odds ratios (OR) and 95% confidence intervals (CI) were obtained using a multiple logistic regression model., Results: A high adherence to the MD is significantly associated with decreased risk of NAFLD (OR: 0.83 95% CI: 0.71-0.98). When the different MD components were examined separately, higher legumes consumption (OR: 0.62 95% CI: 0.38-0.99) and high fish consumption (OR 0.38 95% CI: 0.17-0.85) were reported to be protective against NAFLD., Conclusions: Our study shows that a high adherence to the MD decreases the risk of NAFLD.

Recurrence and second primary cancer (SPC) continue to represent major obstacles to long-term survival in head and neck cancer (HNC). Our aim was to evaluate whether established demographics, lifestyle-related risk factors for HNC and clinical data are associated with recurrence and SPC in HNC. We conducted a multicentre study by using data from five studies members of the International Head and Neck Cancer Epidemiology consortium-Milan, Rome, Western Europe, Sao Paulo, and Japan, totalling 4005 HNC cases with a median age of 59 (interquartile range 52-67). Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for recurrence and SPC. During follow-up, 1161 (29%) patients had recurrence and 343 (8.6%) developed SPC. Advanced tumour stage was associated with increased risk of recurrence in HNC overall (HR = 1.76, 95% CI 1.41-2.19). Women with laryngeal cancer had a reduced risk of recurrence compared to men (HR = 0.39, 95% CI: 0.24-0.74). Concerning predictors of SPC, advanced age (HR = 1.02; 95% CI: 1.00-1.04) and alcohol consumption (> 1 drink per day, HR = 2.11; 95% CI: 1.13-3.94) increased the risk of SPC among patients with laryngeal cancer. Additionally, women were at higher risk of SPC, in HNC overall group (HR = 1.68; 95% CI: 1.13-2.51) and oropharyngeal cancer group (HR = 1.74; 95% CI: 1.02-2.98). Tumour stage and male gender (larynx only) were positive predictors of cancer recurrence in HNC patients. Predictors of SPC were advanced age and alcohol use among laryngeal cancer cases, and female gender for oropharyngeal and HNC overall.

The risk of Helicobacter pylori (HP) infection, as well as gastric cancer (GC), in association with genetic polymorphisms of gene encoding for mucins, has been investigated with contradictory results. We carried out this systematic review and meta-analysis to summarize the relationship between MUC1, MUC5AC, and MUC6 polymorphisms and HP infection, as well as GC risk. We searched MEDLINE, ISI Web of Science, Scopus bibliographic databases and the HuGE Navigator database. Odds ratios (ORs) and 95% confidence interval (CI) were calculated to assess the association between the genetic polymorphisms, and HP/GC risk. A random-effect model was used to calculate the pooled ORs, overall and by ethnicity. Twenty-one studies were included, of which five on HP and 18 on GC, of which two were in common. The meta-analysis of 10 studies on the MUC1 rs4072037 polymorphism and GC risk reported an OR of 0.66 (95% CI: 0.57-0.78) for the dominant model (AG/GG vs. AA). When stratifying for ethnicity, an OR of 0.73 (95% CI: 0.62-0.86) was reported for the Asian population and an OR of 0.48 (95% CI: 0.38-0.61) was reported for the White population. Our study confirms the protective effect of MUC1 rs4072037 polymorphism on the risk of GC under the dominant model. Further studies reporting information on HP status in cases and controls would be required to evaluate whether the protective effect of MUC1 protein might be attributable to a protective effect towards the HP infection, or through different mechanisms.

This study aims to evaluate the effect of ADH1B and ADH7 genotypes on blood acetaldehyde and ethanol levels after alcohol ingestion, and to measure the genotoxic effect of smoking and ethanol on the buccal cells, also controlling for ADH variants. We recruited healthy Italian subjects with at least a moderate history of alcohol consumption. All subjects were given an alcoholic drink of 0.4 g ethanol /kg of body weight. Blood venous samples were collected at baseline, and 30, 60, 90, and 120 minutes after ingestion. Buccal cells were collected before ethanol ingestion. Sixty subjects were enrolled in the study. Individuals with the ADH1B GG genotype had median ethanol levels of 5.0mM (IQR 3.4-7.2), and those with the ADH1B GT/TT genotype had 4.7mM (IQR 4.2-4.8). Corresponding acetaldehyde levels were 1.5μM (IQR 0.7-2.6) for ADH1B GG genotype and 1.6μM (IQR 1.5-1.7) for ADH1B CG/GG genotype. Individuals with the ADH7 CC genotype had median ethanol levels of 5.0mM (IQR 3.3-7.2), while 5.0mM (IQR 4.7-5.6) was in those with the ADH7 CG/GG genotype. Corresponding acetaldehyde levels were 1.5 μM (IQR 0.7-2.6) for ADH7 CC genotype and 1.5 μM (IQR 1.4-1.6) for ADH7 CG/GG genotypes. A non-significant increase in the frequency of karyolitic and pyknotic cells was found in the group of heavy drinkers and current smokers, when compared to the moderate drinkers and the non-smokers. Our study does not support the hypothesis that ADH1B and ADH7 genotypes affect blood ethanol and acetaldehyde concentration., (Copyright © 2017 John Wiley & Sons, Ltd.)

The aim of this study is to evaluate the association between adherence to Mediterranean diet (MD) and gastric cancer (GC). A case-control study was carried out at the Fondazione Policlinico 'A. Gemelli' (Rome, Italy) from 2003 to 2015. A total of 223 incident cases and 223 controls were interviewed. Dietary intake was assessed through a validated food frequency questionnaire that collected information on more than 25 food items. The association between adherence to MD and risk of GC was quantified by calculating Odds Ratios (OR) and 95% confidence intervals (CI). The analysis reports that a higher adherence to MD is associated with a reduced risk of GC (OR: 0.70; 95% CI: 0.61-0.81). A high consumption of vegetables (OR: 0.34; 95% CI: 0.14-0.85), legumes (OR: 0.13; 95% CI: 0.06-0.29), and fish (OR: 0.33; 95% CI: 0.15-0.68), as well as low consumption of meat (OR: 0.29; 95% CI: 0.10-0.85) and alcohol (OR: 0.46; 95% CI: 0.24-0.90) are consistently related to a lower risk of GC. Our study indicates a protective role of the MD eating pattern and MD individual components against GC. Our results showed a beneficial role of high vegetable, legume, and fish consumption, along with low intake of alcohol and meat in the development of GC.

Background: This study evaluated whether demographics, pre-diagnosis lifestyle habits and clinical data are associated with the overall survival (OS) and head and neck cancer (HNC)-specific survival in patients with HNC., Patients and Methods: We conducted a pooled analysis, including 4759 HNC patients from five studies within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Cox proportional hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated including terms reported significantly associated with the survival in the univariate analysis., Results: Five-year OS was 51.4% for all HNC sites combined: 50.3% for oral cavity, 41.1% for oropharynx, 35.0% for hypopharynx and 63.9% for larynx. When we considered HNC-specific survival, 5-year survival rates were 57.4% for all HNC combined: 54.6% for oral cavity, 45.4% for oropharynx, 37.1% for hypopharynx and 72.3% for larynx. Older ages at diagnosis and advanced tumour staging were unfavourable predictors of OS and HNC-specific survival. In laryngeal cancer, low educational level was an unfavourable prognostic factor for OS (HR = 2.54, 95% CI 1.01-6.38, for high school or lower versus college graduate), and status and intensity of alcohol drinking were prognostic factors both of the OS (current drinkers HR = 1.73, 95% CI 1.16-2.58) and HNC-specific survival (current drinkers HR = 2.11, 95% CI 1.22-3.66). In oropharyngeal cancer, smoking status was an independent prognostic factors for OS. Smoking intensity (>20 cigarettes/day HR = 1.41, 95% CI 1.03-1.92) was also an independent prognostic factor for OS in patients with cancer of the oral cavity., Conclusions: OS and HNC-specific survival differ among HNC sites. Pre-diagnosis cigarette smoking is a prognostic factor of the OS for patients with cancer of the oral cavity and oropharynx, whereas pre-diagnosis alcohol drinking is a prognostic factor of OS and HNC-specific survival for patients with cancer of the larynx. Low educational level is an unfavourable prognostic factor for OS in laryngeal cancer patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The aims of this study were to identify the best threshold value for the real-time PCR method in detecting the presence of Legionella pneumophila in water samples, and to evaluate the prognostic significance of negative results obtained with the molecular method. From 2011 to 2014, 77 water samples were collected from hospital wards of a large University teaching hospital in Rome (Italy) and screened for L.pneumophila by the standard culture method and by real-time PCR. The high sensitivity and negative predictive value of real-time PCR make this method suitable as a quick screening tool to exclude the presence of L. pneumophila in water samples in the hospital setting.

Background: The purpose of this study is to evaluate whether demographics, lifestyle habits, clinical data and alcohol dehydrogenase polymorphisms rs1229984 and rs1573496 associated with first primary head and neck (HNC) are associated with overall survival, recurrence, and second primary cancer (SPC)., Methods: We conducted a follow-up study in five centres including 801 cases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for overall survival, recurrence and SPC., Results: Five-years overall survival was 62% for HNC cases, 55% for oral cavity, 53% for oropharynx, 41% for hypopharynx, and 71% for larynx. Predictors of survival were older ages (HR=1.18 for 5 years increase; CI: 1.07-1.30), higher tumour stage (HR=4.16; CI: 2.49-6.96), and high alcohol consumption (HR=3.93; CI: 1.79-8.63). A combined therapy (HR=3.29; CI: 1.18-9.13) was associated with a worst prognosis for oral cavity cancer. The only predictor was higher tumour stage (HR=2.25; CI: 1.26-4.03) for recurrence, and duration of smoking (HR=1.91; CI: 1.00-3.68) for SPC. ADH1B rs1229984 polymorphism HRs for HNC and oesophageal cancer death and for alcohol related cancer death were 0.67 (95% CI: 0.42-1.08), and 0.64 (95% CI: 0.40-1.03), respectively., Conclusions: The survival expectation differs among HNC sites. Increasing age and stage, and high alcohol consumption were unfavourable predictors of HNC survival overall. Duration of tobacco consumption before the first primary tumour was a risk factor for SPC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: The need to integrate clinical and public health training of medical students is increasingly important. Future physicians need to be able to deal with new, complex and growing public health challenges., Materials and Methods: A literature search was performed through Pubmed to identify the conceptual reference framework. Meetings were carried out to identify the most appropriate modalities and priorities required for drafting the project, to identify the skills to be acquired by students, to decide on teaching formats and methods to assess student learning, to draw up the teaching schedule, to define the statistical methods to be used to assess student satisfaction, and to perform the statistical analysis of results. Training in hospital hygiene and environmental safety was carried out through presentation of a relevant case. After being divided into groups the students attended the three units (Environmental Microbiology, Environmental Xenobiotics, Genetic Epidemiology and Molecular Biology) of the Hygiene Section of a Public Health Institute. Training in Organization and Health Programming involved presentation of a set of indicators for the definition of objectives and assessment of health systems or services., Results: The literature search led to the identification of the relevant literature. With regard to student satisfaction, 96% of those who replied to the questionnaire gave an overall positive review of the training course (at least 3 on a scale from 1 to 5)., Conclusions: the overall high level of student satisfaction suggests that the proposed model may be exportable. Further developments will be the assessment of trends regarding functioning of the organizational model and perceived teaching quality.

Gastric cancer affects about one million people per year worldwide, being the second leading cause of cancer mortality. The study of its etiology remains therefore a global issue as it may allow the identification of major targets, besides eradication of Helicobacter pylori infection, for primary prevention. It has however received little attention, given its comparatively low incidence in most high-income countries. We introduce a consortium of epidemiological investigations named the 'Stomach cancer Pooling (StoP) Project'. Twenty-two studies agreed to participate, for a total of over 9000 cases and 23 000 controls. Twenty studies have already shared the original data set. Of the patients, 40% are from Asia, 43% from Europe, and 17% from North America; 34% are women and 66% men; the median age is 61 years; 56% are from population-based case-control studies, 41% from hospital-based ones, and 3% from nested case-control studies derived from cohort investigations. Biological samples are available from 12 studies. The aim of the StoP Project is to analyze the role of lifestyle and genetic determinants in the etiology of gastric cancer through pooled analyses of individual-level data. The uniquely large data set will allow us to define and quantify the main effects of each risk factor of interest, including a number of infrequent habits, and to adequately address associations in subgroups of the population, as well as interaction within and between environmental and genetic factors. Further, we will carry out separate analyses according to different histotypes and subsites of gastric cancer, to identify potential different risk patterns and etiological characteristics.

Objectives/hypothesis: Sudden sensorineural hearing loss (SSNHL) is strictly related to inner ear vascular injuries and recently to some atherosclerotic risk factors. The pathogenic role of inflammatory molecules in atherosclerosis is well established. However, there is little knowledge about the potential role of inflammatory cytokines and adhesion molecules on SSNHL etiology., Study Design: The aim of this study was to evaluate the role of proinflammatory genetic polymorphisms of the MCP-1 (CCL2), E-selectin, and interleukin (IL)-6 gene in SSNHL patients., Methods: We evaluated the frequency and distribution of selected single nucleotide polymorphisms of the MCP-1 (CCL2), E-selectin, and IL-6 gene in 87 SSNHL patients and 107 healthy controls., Results: Our results did not show significant difference between the compared groups for MCP-1 and E-selectin genes, whereas a significant difference was reported for the IL-6 gene (P < .0001)., Conclusions: The main finding of our study is that the 174G/G polymorphism (with a wider distribution of wt/wt genotype in SSNHL patients than in the healthy controls) of the IL-6 gene is significantly associated with the risk of SSNHL, which is consistent with a previous finding on serum levels of IL-6 in SSNHL. It is possible that the variant acts as a triggering agent of different lipidemia-related phenotypes. Both the -174G/G polymorphism and elevated IL-6 levels in SSNHL patients could suggest that IL-6 plays a role in the inner ear involvement by atherosclerotic inflammatory events., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Aim. The aim of our study was to assess whether selected single nucleotide polymorphisms of CYP1A1 and 2E1, GSTM1, GSTT1, and SULT1A1 influence susceptibility towards HCC, considering their interaction with cigarette smoking. Methods. We recruited HCC cases and controls among patients admitted to the hospital "Agostino Gemelli," from January 2005 until July 2010. Odds ratios (OR) of HCC were derived from unconditional multiple logistic regression. Gene-gene and gene-smoking interaction were quantified by computing the attributable proportion (AP) due to biological interaction. Results. The presence of any CYP2E1 (*) 5B variant allele (OR: 0.23; 95% CI: 0.06-0.71) and CYP2E1 (*) 6 variant allele (OR: 0.08; 95% CI: 0.01-0.33) was inversely related to HCC. There was a borderline increased risk among carriers of combined CYP1A1 (*) 2A and SULT1A1 variant alleles (OR: 1.67; 95% CI: 0.97-3.24). A significant biological interaction was observed between GSTT1 and smoking (AP = 0.48; 95% CI: 0.001-0.815), with an OR of 3.13 (95% CI: 1.69-5.82), and borderline significant interaction was observed for SULT1A1 and smoking (AP = 0.36; 95% CI: -0.021-0.747), with an OR of 3.05 (95% CI: 1.73-5.40). Conclusion. CYP2E1 (*) 5B and CYP2E1 (*) 6 polymorphisms have a favourable effect on the development of HCC, while polymorphisms of GSTT1 and SULT1A1 might play role in increasing the susceptibility among smokers.

The aim of this study was to identify the clinical, demographic, lifestyle factors and selected genetic polymorphisms that affect the susceptibility towards Helicobacter pylori (H. pylori) infection in gastric cancer patients. Histological confirmed gastric adenocarcinoma cases that underwent curative gastrectomy between 2002 and 2012 were included. Gastric biopsy samples were obtained to determine the H. pylori status, and further cagA status and vacA m and s genotypes by polymerase chain reaction. Patients were interviewed with structured questionnaires, and blood samples were collected for EPHX1, GSTM1, GSTT1, IL1B, IL1-RN, MTHFR and p53 genotyping. Proportions were compared in univariate analysis, while the relation between putative risk factors and H. pylori status and genotype were measured using logistic regression analysis. One hundred forty-nine gastric cancer patients were included, of which 78.5% were H. pylori positive. Among positive patients 50% were cagA+, 72.5% vacA m1 and 80.7% vacA s1. The presence of cagA was less frequent among vacA m1 (p = 0.031) and vacA s1 (p = 0.052) subtypes. The presence of father history for any cancer was a significant risk factor for H. pylori infection [adjusted odds ratio (OR) = 8.18, 95% confidence interval (CI) 1.04-64.55]. EPHX1 exon 3 T > C (OR = 0.35, CI 95% 0.13-0.94), IL1B-511 T > C (OR = 0.38, CI 95% 0.15-0.97) and IL1-RN VNTR (OR = 0.19, CI 95% 0.06-0.58) polymorphisms were protective towards H. pylori infection in the univariate analysis. Wine consumption was associated with higher risk of carrying the H. pylori vacA m1 virulent subtype (p = 0.034). Lastly, cardiovascular diseases were less common among cagA positive subjects (p = 0.023). Father history of any cancer is a risk factor for H. pylori infection. Polymorphisms in IL1B-511, IL1-RN and EPHX1 exon 3 genes might be protective towards H. pylori infection.

The oxidative stress is a key issue in the etiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to evaluate the effect of metabolic gene polymorphisms involved in the oxidative stress (GSTT1, GSTM1, SULT1A1, CYP2E1, and 1A1), lifestyle and nutrition aspects, and their interaction, on the risk of NAFLD. We enrolled 294 cases and 359 controls, and collected demographics, anthropometric, lifestyle, and nutrition data. A subgroup of NAFLD provided additional data on nutrients and on physical activity engagement. Each patient provided a blood sample for DNA extraction and genotyping. Clinical and laboratory data were collected from cases. Multivariable analysis shows a significant protective effect of age, gender, and moderate drinking habits on the risk of NAFLD, while an increased risk for greater consumption of fruit and grilled meat or fish. Significant interactions were reported between alcohol consumption, fruit intake, grilled meat and fish, and selected genetic variants. From the subgroup analysis, a moderate/high consumption of fat and/or grilled meat/fish, and a high consumption of white meat increase the risk of NAFLD. Engaging any physical activity at least 1 time/week halves the risk of NAFLD. Besides confirming the beneficial effect of moderate alcohol intake and regular physical activity, and the increased risk associated with high fruit and fat intake, for the first time, we report a detrimental effect of grilled food on NAFLD risk. An effect modification by selected gene variants increases the risk in combination with fruit and grilled food intake.

Background: Survival of patients after curative surgical resection for gastric cancer (GC) remains poor, thus emphasizing the need for better definition of prognostic factors to improve the long-term course of disease., Methods: From 1999 to 2009, 110 patients had curative-intent gastrectomy for adenocarcinoma. Clinicopathological features, Helicobacter pylori infection, dietary habits and lifestyle, and the presence of proinflammatory gene polymorphisms were evaluated., Results: At the end of follow-up, 55 deaths had occurred, 48 of them due to GC, whereas the median overall survival (OS) and disease-free survival (DFS) were 62 and 51 months, respectively. From the Kaplan-Meier analysis and log-rank test, statistically significant differences in OS and DFS were found for tumor site (only for DFS), tumor size, lymph node metastasis ratio (NR), and tumor-node-metastasis stage, but not for age, comorbidity, H. pylori infection, cigarette smoking, and IL1B or TNFA polymorphisms. Multivariable Cox regression analysis revealed NR was an independent prognostic factor for OS and DFS. Cardia tumor and patient age 65 years or older were also independent prognostic factors for OS and DFS., Conclusions: Tumor-related factors remain strongest predictors of survival in GC patients after surgery. Particularly, NR was an effective feature in identifying patients at high risk for adverse outcome., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Several epidemiological studies have shown a positive association between adult height and cancer incidence. The only study conducted among women on mouth and pharynx cancer risk, however, reported an inverse association. This study aims to investigate the association between height and the risk of head and neck cancer (HNC) within a large international consortium of HNC. We analyzed pooled individual-level data from 24 case-control studies participating in the International Head and Neck Cancer Epidemiology Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated separately for men and women for associations between height and HNC risk. Educational level, tobacco smoking, and alcohol consumption were included in all regression models. Stratified analyses by HNC subsites were performed. This project included 17,666 cases and 28,198 controls. We found an inverse association between height and HNC (adjusted OR per 10 cm height = 0.91, 95% CI 0.86-0.95 for men; adjusted OR = 0.86, 95% CI 0.79-0.93 for women). In men, the estimated OR did vary by educational level, smoking status, geographic area, and control source. No differences by subsites were detected. Adult height is inversely associated with HNC risk. As height can be considered a marker of childhood illness and low energy intake, the inverse association is consistent with prior studies showing that HNC occur more frequently among deprived individuals. Further studies designed to elucidate the mechanism of such association would be warranted.

Background: The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence., Patients and Methods: We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits., Results: Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline., Conclusion: We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.

Background: Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far., Methods: One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan-Meier analysis and Cox proportional hazard regression model., Results: Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 - 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium., Conclusions: Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study's sample size, further studies are required to confirm our findings.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions being the most common cause of chronic liver disease in Western countries. The Apolipoprotein E (ApoE) gene has three major isoforms encoded by the ε2, ε3, and ε4 alleles, with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. The role of apoE genotypes on NAFLD has been previously investigated with conflicting results. Our hospital-based case-control study conducted in Italy aims to explore the effect of the apoE genotypes on NAFLD risk and their effect on the clinical features of NAFLD patients. 310 NAFLD cases and 422 controls were genotyped for apoE. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) from logistic regression were used to explore the relationship between NAFLD and apoE genotypes, as well as their interaction with selected demographic and lifestyle factors. ApoE ε4 allele carriers showed a statistically significant two-fold reduction of NAFLD risk (OR = 0.51, 95% CI: 0.28-0.93) compared with ε3 homozygotes. A statistically significant lower HDL cholesterol level was observed for ApoE ε4 carriers if compared with ε3/ε3 genotype or ApoE ε2 carriers with a nearly linear decreasing trend from ApoE ε2 to ApoE ε4 carriers. Our study reports for the first time a protective effect of the ε4 allele towards NAFLD that might be attributable to its role in the regulation of hepatic triglycerides rich very low-density lipoproteins secretion.

The purpose of this report is to review the relationship between genetic polymorphisms involved in carcinogen metabolism, alcohol metabolism and cell-cycle control with the risk of head and neck cancer. The review was performed on available studies on genetic polymorphisms and head and neck cancer (HNC) published in PubMed up to September 2011. 246 primary articles and 7 meta-analyses were published. Among these, a statistically significant association was reported for glutathione S-transferases (GSTM1), glutathione S-transferases (GSTT1) and human microsomal epoxide hydrolase (EPHX1) genes. An increased risk for HNC was also associated reported for P53 codon 72 Pro/Pro, ALDH2 and three variants of the ADH gene: ADH1B (rs1229984), ADH7 (rs1573496) and ADH1C (rs698).

Increasing evidence suggests that physical activity could prevent cancer, but scanty data is available on head and neck cancer (HNC). The aim of our study is to clarify the effect of recreational physical activity (rPA) on HNC. We analyzed data from four case-control studies, including 2,289 HNC cases and 5,580 controls. rPA was classified as: none/low (reference group), moderate and high. We calculated summary Odds Ratios (ORs) by pooling study-specific ORs. Overall, moderate rPA was associated with 22% lower risk of HNC compared to those with none or very low rPA levels [OR = 0.78, 95% Confidence Interval (95% CI): 0.66, 0.91]. Moderate rPA is associated with reduced risk of oral (OR = 0.74, 95% CI: 0.56, 0.97) and pharyngeal cancer (OR = 0.67, 95% CI: 0.53, 0.85), as well as high rPA levels (OR = 0.53, 95% CI: 0.32, 0.88 for oral cavity, OR = 0.58, 95% CI: 0.38, 0.89 for pharynx). High rPA levels, however, is associated with higher risk of laryngeal cancer (OR = 1.73, 95% CI: 1.04, 2.88). Stratified analyses showed that such inverse association between moderate rPA and HNC was more evident among males (OR = 0.75, 95% CI: 0.62, 0.90), subjects ≥45 years (OR = 0.78, 95% CI: 0.66, 0.93), and ever smokers and ever drinkers (OR = 0.72, 95% CI: 0.59, 0.88). High rPA significantly reduces HNC risk among subject ≥45 years (OR = 0.66, 95% CI: 0.48, 0.91). Promoting rPA might be inversely associated with HNC.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Competing Interests: The authors have declared that no competing interests exist.

Background: The apolipoprotein E gene (apoE) has three major isoforms encoded by the ε2, ε3, and ε4 alleles, with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterolemia and head and neck cancer (HNC) has been previously reported, although the relationship between apoE genotypes and HNC has not been explored to date., Methods: Four hundred and seventeen HNC cases and 436 hospital controls were genotyped for apoE polymorphisms. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) from logistic regression were used to explore the relationship between HNC and putative risk factors. A gene-environment interaction analysis was done., Results: A borderline significant 40% decreased HNC risk (OR, 0.58; 95% CI, 0.31-1.05) was observed for individuals carrying at least one ε2 allele. Females carrying at least one ε2 allele showed a 60% risk reduction (OR, 0.43; 95% CI, 0.21-0.90) for HNC compared with ε3 homozygotes. A statistically significant interaction was found between alcohol use and the ε4 allele (P for interaction = 0.04), with a 2-fold increased risk (OR, 2.06; 95% CI, 0.95-4.48) among ever drinkers with an ε4 allele, with respect to ε3 homozygote nondrinkers., Conclusions: Our study provides novel evidence of a possible protective effect of the ε2 allele against HNC, probably due to its increased antioxidant properties., Impact: According to our results, apolipoprotein E may play a different role in carcinogenesis other than its well-known role in regulating blood serum cholesterol levels., (©2010 AACR.)

Background: The purpose of this study is to analyze the combined effects of selected p53 and p73 polymorphisms and their interaction with lifestyle habits on squamous cell carcinoma of the head and neck (SCCHN) risk and progression in an Italian population., Methods: Two hundred and eighty-three cases and 295 hospital controls were genotyped for p53 polymorphisms on exon 4 (Arg72Pro), intron 3 and 6, and p73 G4C14-to-A4T14. Their association with SCCHN was estimated using a logistic regression analysis, while a multinomial logistic regression approach was applied to calculate the effect of the selected polymorphisms on SCCHN different sites (oral cavity, oropharynx, hypopharynx and larynx). We performed an haplotype analysis of the p53 polymorphisms, and a gene-gene interaction analysis for the combined effects of p73 G4C14-to-A4T14 and p53 polymorphisms., Results: We found a significant increased risk of SCCHN among individuals with combined p73 exon 2 G4A and p53 intron 3 variant alleles (OR = 2.22, 95% CI: 1.08-4.56), and a protective effect for those carrying the p53 exon 4-p53 intron 6 diplotype combination (OR = 0.67; 95% CI: 0.47-0.92). From the gene-environment interaction analysis we found that individuals aged < 45 years carrying p73 exon 2 G4A variant allele have a 12.85-increased risk of SCCHN (95% CI: 2.10-78.74) compared with persons of the same age with the homozygous wild type genotype. Improved survival rate was observed among p53 intron 6 variant allele carriers (Hazard Ratio = 0.51 (95% CI: 0.23-1.16)., Conclusion: Our study provides for the first time evidence that individuals carrying p53 exon 4 and p53 intron 6 variant alleles are significantly protected against SCCHN, and also shows that an additional risk is conferred by the combination of p73 exon 2 G4C14-to-A4T14 and p53 intron 3 variant allele. Larger studies are required to confirm these findings.

The p53 protein and its functional homologue p73 share several functions in modulating cell-cycle control and apoptosis. Based on the functional interaction between p53 and p73 in carcinogenesis, we investigated the combined effect of p73 G4C14-to-A4T14 and p53 gene polymorphisms and their interaction with selected environmental factors, on the risk for gastric cancer in a hospital-based case-control study conducted in Italy. The effect of these polymorphisms on cancer progression was also investigated. One hundred and fifteen gastric cancer cases and 295 hospital controls were genotyped for p73 G4C14-to-A4T14, and p53 exon 4 (Arg72Pro), intron 3 and intron 6 polymorphisms. An increased risk for gastric cancer was found to be associated with the inheritance of the p73 homozygous variant genotype among the gastric cancer intestinal histotype (odds ratio (OR)=6.75; 95% confidence interval (95% CI)=1.88-24.24). An effect modification of the p73 variant allele by gender was observed [(OR=2.82; 95%CI=1.24-6.40) among females, versus an OR of 0.70 (95%CI=0.32-1.54) among males; p-value for homogeneity among strata estimates =0.03]. Gene-gene interaction analyses demonstrated that individuals with combined p53 exon 4 and intron 6 variant alleles are borderline significantly protected from gastric cancer (OR=0.52; 95% CI=0.26-1.07; p-value for interaction =0.005), which was confirmed by the haplotype analysis. Finally, a poorer survival was observed among carriers of the variant allele of p53 intron 6 if compared with those carrying both wild-type alleles (p-value for log-rank test =0.02). This study shows that the p73 G4C14-to-A4T14 polymorphism may be a risk factor for gastric cancer, as reported from other studies in different tumour sites among Caucasians. Along with the protective effect of p53 exon 4-intron 6 allelic variants, already noted for breast and lung cancer, our results require confirmation from larger studies.

Purpose: As risk-modifiers of alcohol and tobacco effects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN)., Methods: A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% confidence interval (CI)., Results: SCCHN risk was associated with high-levels of alcohol intake [OR = 3.50 (95%CI: 1.93-6.35) and OR = 6.47 (95%CI: 2.92-14.35) for 19-30 g/day and >30 g/day, respectively], cigarette smoking [OR = 3.47 (95%CI: 1.88-6.41) and OR = 7.65 (95%CI: 4.20-13.90) for 1-25 and >25 pack-years of smoking, respectively] and low-fruit and vegetables consumption (OR = 2.45; 95%CI: 1.53-3.92). No differences were observed for the genotypes or haplotypes distributions among cases and controls, and no biological interaction emerged from gene-gene and gene-environment interaction analyses. An attributable proportion (AP) due to biological interaction of 0.65 (95%CI: 0.40-0.90) was detected for heavy drinkers with a low intake of fruit and vegetables, and an AP of 0.40 (95%CI: 0.10-0.72) resulted forever smokers with low fruit and vegetables consumption., Conclusions: Even in presence of high alcohol consumption or cigarette smoking, a high intake of fruit and vegetables might prevent the development of around one quarter of SCCHN cases. The lack of interaction between the studied polymorphisms and the environmental exposures suggests that chronic consumption of tobacco and alcohol overwhelm enzyme defences, irrespective of genotype.

Background: The distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population., Methods: One hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis., Results: Gastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27-3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03-5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45-9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22-1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27-5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45-1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52-5.93) and an AP of 52%., Conclusion: GSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individual's susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies.

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case-control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98-2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07-5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05-4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12-7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individual's susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.