Small bowel capsule endoscopy for the investigation of obscure gastrointestinal bleeding: When we should do it and what should we expect.

Obscure gastrointestinal bleeding is defined as bleeding of unknown origin that persists or recurs (i.e. recurrent or persistent iron deficiency anemia, fecal occult blood test positivity or visible bleeding) after a negative initial workout that necessarily includes gastroscopy and colonoscopy. In clinical practice, small bowel capsule endoscopy is recommended as a third stage examination in these patients, since it is a simple, safe, non-invasive and reliable test. To date there are three available small bowel capsule systems that have gained FDA approval and their diagnostic yield has shown to be superior to other diagnostic modalities for the investigation of the small bowel in patients with obscure gastrointestinal bleeding. The test should be performed as close to the bleeding episode as possible and the administration of a purgative bowel preparation before the administration of capsule endoscopy is recommended by the European Society of Gastrointestinal Endoscopy (ESGE). Issues that still remain to be solved are the definition of bleeding lesions and what really represents a positive finding, as well as the question of whether the outcome of patients with obscure gastrointestinal bleeding is altered after the test, i.e. to better define subgroups of patients that will mostly benefit from capsule endoscopy. In the future small bowel capsule endoscopy might be able to get guided, while tissue samples might be available as well. (Acta gastro-enterol. belg., 2016, 79, 355-362).

Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Serotonin transporter and G protein beta 3 subunit gene polymorphisms in Greeks with irritable bowel syndrome.

BACKGROUND: Polymorphisms in the serotonin transporter (SERT) and G protein ß3 subunit (GNB3) genes might contribute to the pathophysiology of irritable bowel syndrome (IBS). Association studies of SERT and GNB3 polymorphisms and IBS have shown diverse results among different populations, which might be due to subject composition differences. AIMS: The aim of the study was to assess the potential association between SERT and GNB3 polymorphisms and IBS in Greeks. METHODS: A total of 124 patients with IBS diagnosed according to the Rome III criteria and 238 healthy individuals were included in the study. SERT and GNB3 gene polymorphisms were genotyped using polymerase chain reaction-based methods. RESULTS: It was shown that the frequencies of the SS genotype and S allele of the serotonin transporter polymorphism were significantly associated with IBS (P = 0.0314 and P = 0.019, respectively). TT genotype and T allele frequencies of G protein ß3 subunit showed also significant difference between the IBS patients and healthy controls IBS (P = 0.0163 and P = 0.0001, respectively). None of the clinical symptoms analyzed was significantly associated with the polymorphisms tested. CONCLUSIONS: The results suggest that SERT and GNB3 gene polymorphisms might be associated with irritable bowel syndrome predisposition in Greeks.

Impact of beta-glucan on the faecal microbiota of polypectomized patients: a pilot study.

Beta-glucans are polysaccharides present in the cell walls of higher plants, in the seeds of some cereals, and certain yeasts and fungi also produce them. It is suggested that they exhibit, among many other health benefits, protective effects against carcinogenesis in the colon, but there is not enough human data to support this. The aim of the study was to determine the effect of barley-derived beta-glucan in the gut microbiota of polypectomized patients. Subjects were randomly assigned to consume 125 g of bread per day with beta-glucan (3 g/d), or without (placebo group), for 3 months. Thirty-three polypectomized men and women (mean age 57.6 years) were recruited into the study, but only 20 completed. Subjects did not consume any probiotics, prebiotics or antibiotics 2 months prior the intervention, or during the study. Stool samples were collected at baseline, on days 30 and 90 of intervention, as well as 2 weeks after the intervention, for enumeration of total aerobes and anaerobes, coliforms, E. coli, enterococci, Bacteroides spp., Clostridium perfringens, bifidobacteria, lactobacilli and Candida spp. Faecal bacterial enzyme activity (beta-glucuronidase and beta-glucosidase), pH, faecal moisture and the concentration of volatile fatty acids in the faeces were measured. Gastrointestinal symptoms were also recorded. Overall, no significant differences were observed in bacterial viable counts between the two feeding groups. Group specific analysis for ß-glucan group revealed significantly decreased total coliform counts on the 30th day of the trial compared to the baseline (p = 0.041). Clostridium perfringens concentration increased without reaching statistical significance, on the 30th day, while it decreased significantly on the 90th day of the intervention compared to the 30th day (p = 0.016). An increase was noted in the molar ratio of acetate on the 90th day of the trial compared to placebo (p = 0.018). The molar ratio of butyrate presented a trend to increase on the 30th day, which decreased (p = 0.013) on the 90th day and then increase 2 weeks after the intervention (p = 0.017) compared to placebo. A decrease was recorded in the ß-glucan group in the bloating and abdominal pain score after the 30th day of the intervention (Day 30-37) compared to placebo. During ß-glucan administration we did not observe any changes on beta-glucuronidase or beta-glucosidase activity, faecal pH, or on faecal moisture.

Similar response to adalimumab in patients with active Crohn's disease either naive to biologic agents or with prior loss of response or intolerance to infliximab.

UNLABELLED: The aim of this study was to investigate the efficacy of adalimumab, in patients with moderately active Crohn's disease (CD), either naive to biologic agents or with prior loss of response or intolerance to infliximab. MATERIAL AND METHOD: A total number of 30 patients with moderately active CD (14 men, 16 women, aged 38.5 +/- 14.4 yr) either naive to biologic agent treatment (19 pts (65%)) or with loss of response or intolerance to infliximab (11 pts (35%)), were enrolled to 4-wk trial with treatment with subcutaneous adalimumab 160 mg injection at week 0, 80 mg at week 2 and then 40 mg every other week. Outcome measures included the ability to tolerate adalimumab and clinical remission (defined as a CDAI score < or =150 points) and clinical response (defined as a decrease in the CDAI) > or =70 points). Eleven patients (37%) were smokers, 5(16%) ex-smokers and 14 (47%) non-smokers. Five patients (16%) had a positive family history for IBD. Duration of disease was 10.7 +/- 8.1 yr. Coexistence of extraintestinal manifestations was noticed in 12 (40%) patients. Vienna Classification of CD was A1=24 (80%), A2=6 (20%), L1=8 (26.7%), L2=6 (20%), L3=15 (50%), L4=1 (3.3%), B1=15 (50%), B2=5 (16.7%), B3=10 (33.3%). RESULTS: Remission was observed in 19 (63.3%) and clinical response in 9 (30%) patients. Two patients (6.7%) showed no response. No significant differences between patients with loss of response or intolerance to infliximab and the group of naive patients were noticed. Comparison between smokers and non smokers revealed significant difference in the response rate in favour of non-smokers (P < 0.002). A trend (P = 0.064) towards a significant difference in the response rate of the group of smokers according to the number of cigarettes smoked per day was observed. Patients with short duration of disease (<10 yr) had significantly better response compared to the group of patients with long (>10 yr) duration of disease. Similarly, patients with extraintestinal manifestations showed significantly better response (P = 0.044). None of the patients in both groups experienced acute or delayed hypersensitivity reactions during treatment with adalimumab. CONCLUSION: Adalimumab is well tolerated and appears to be a beneficial option for patients with CD who have not previously treated with biologic agents or have lost their response to, or cannot tolerate infliximab, with non-smokers, patients with short duration of CD, and patients with extraintestinal manifestations having a better clinical response.

Sedation in digestive endoscopy: the Athens international position statements.

BACKGROUND: Guidelines and practice standards for sedation in endoscopy have been developed by various national professional societies. No attempt has been made to assess consensus among internationally recognized experts in this field. AIM: To identify areas of consensus and dissent among international experts on a broad range of issues pertaining to the practice of sedation in digestive endoscopy. METHODS: Thirty-two position statements were reviewed during a 1 (1/2)-day meeting. Thirty-two individuals from 12 countries and four continents, representing the fields of gastroenterology, anaesthesiology and medical jurisprudence heard evidence-based presentations on each statement. Level of agreement among the experts for each statement was determined by an open poll. RESULTS: The principle recommendations included the following: (i) sedation improves patient tolerance and compliance for endoscopy, (ii) whenever possible, patients undergoing endoscopy should be offered the option of having the procedure either with or without sedation, (iii) monitoring of vital signs as well as the levels of consciousness and pain/discomfort should be performed routinely during endoscopy, and (iv) endoscopists and nurses with appropriate training can safely and effectively administer propofol to low-risk patients undergoing endoscopic procedures. CONCLUSIONS: While the standards of practice vary from country to country, there was broad agreement among participants regarding most issues pertaining to sedation during endoscopy.

Endoscopic sedation in Greece: results from a nationwide survey for the Hellenic Foundation of gastroenterology and nutrition.

BACKGROUND AND STUDY AIMS: Recent surveys regarding practices in sedation during endoscopic procedures are limited, particularly in Greece where they are nonexistent. This survey was designed to provide national data on sedation practices in Greece. METHODS: A 27-item survey regarding practices of endoscopy and sedation was mailed nationwide to 502 members of the Hellenic Society of Gastroenterology. RESULTS: A total of 201 questionnaires were returned (40%). Survey respondents performed an average of 48 oesophagogastroduodenoscopies (EGD) and 35 colonoscopies per month. 50 of the respondents, who perform endoscopic retrograde cholangiopancreatography (ERCP), conducted an average of 10 ERCP per month. 15 of the respondents, who perform endoscopic ultrasound (EUS), conducted an average of 6 EUS per month. Respondents administered sedation intravenously in 64% of EGD, 78% of colonoscopies, 100% of ERCP and 100% of EUS. 125 of the respondents (62.1%) reported the use of synergistic sedation (benzodiazepines plus opioids), 71 of the respondents (35.3%) reported the use of benzodiazepines alone and 68 of the respondents (33.8%) reported the use of propofol based sedation in selected cases (more than one response was permitted). In most cases, propofol administration was directed by an anaesthesiologist. The majority of the respondents monitored vital signs and pulse oximetry (90% and 96%, respectively). CONCLUSION: The use of sedation and physiologic monitoring in Greece is now standard practice during endoscopy. Benzodiazepines, either alone or combined with an opioid, are used by the majority of endoscopists, while propofol is used in selected cases, mainly in the presence of an anaesthesiologist.

Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis.

BACKGROUND: Endotoxaemia is commonly seen in cirrhotic patients with ascites and this may be associated with increased portal pressure. AIM: To investigate the effect of intestinal decontamination on liver haemodynamics in alcohol-related cirrhotic patients with ascites. METHODS: We included 30 patients. At day 0, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed. Patients received rifaximin (1200 mg/day) for 28 days. At day 29, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed again. RESULTS: Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45(0-3.1) vs. 0.7(0-2.7), P < 0.0001] and splanchnic circulation [1.8(0-3.4) vs. 0.8(0-2.1), P < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (P = 0.001) was not noted at day 29 (P = 0.137). HVPG measurement was possible in 28 patients. Median (range) HVPG values were 18 mmHg (12.7-26.3) on day 0 vs. 14.7 mmHg (7-20) on day 29 (P < 0.0001). HVPG decreased after rifaximin in 23, remained stable in two and increased in three patients. CONCLUSION: Hepatic venous pressure gradient values decreased significantly after intestinal decontamination with rifaximin in patients with alcohol-related decompensated cirrhosis and this might have been achieved through significant reduction of plasma endotoxin levels.

Comparison of T- and Z-score in identifying risk factors of osteoporosis in inflammatory bowel disease patients.

OBJECTIVE: Most studies have shown contradictory results regarding predictive factors of osteoporosis in inflammatory bowel disease (IBD). Since in these studies either T- or Z-scores has been used, our aim was to compare T- and Z-score in identifying risk factors of osteoporosis in IBD patients. MATERIALS AND METHODS: Bone density was measured by dual X-ray absorptiometry (DXA) at L2-L4 of the spine and femoral neck in 122 patients. Twenty-two clinical parameters were recorded prior to DXA and evaluated by univariate and multivariate analysis. RESULTS: On multivariate analysis, cumulative steroid dose was a predictive factor of femoral neck T-score (p<0.001) and Z-score (p=0.001). Age was a predictive factor of femoral neck T-score (p<0.001). BMI was a predictive factor of femoral neck Z-score (p=0.03). None of the other 19 variables tested had any predictive value for bone density. Age >or=55 years was a risk factor of low femoral neck T-score (OR 5.08, 95% CI 1.90-13.57, p=0.001), as was cumulative dose of prednisolone >or=5 g (OR 3.41, 95% CI 1.50-7.73, p=0.004). CONCLUSIONS: There is a discordance of results depending on whether T- or Z-scores are used in analysis. Among 22 parameters, cumulative steroid dose and age proved to be the most important factors.

Epithelial cell turnover, p53 and bcl-2 protein expression during oncogenesis of early and advanced gastric cancer in a Western population.

OBJECTIVES: To investigate epithelial cell turnover alterations, and p53, bcl-2 protein expression during development of early and advanced gastric cancer in a Western population. METHODS: We investigated cell apoptosis and proliferation rates, p53 and bcl-2 protein expression in 17 early and 34 advanced gastric carcinomas and in the adjacent non-dysplastic mucosa. Cell proliferation, p53 and bcl-2 expression were detected immunohistochemically using MIB-1, anti-p53 and anti-bcl-2 monoclonal antibodies. Apoptosis was measured by TUNEL. The rate of the positive stained cells (labelling index) was count using image analysis technique. RESULTS: No difference was observed of either apoptotic (10 vs. 11) or proliferation (35 vs. 25) index between early and advanced cancers. However, the apoptotic index was significantly higher in intestinal type advanced tumors. While both apoptotic and proliferation indices were significantly higher in tumors than in the adjacent mucosa, no difference was observed of either apoptotic (2 vs. 2) or proliferation (8 vs. 13) index between the tissues adjacent to early and advanced tumors. p53 protein expression was significantly higher in advanced cancers (7 vs. 5, p=0.001) and in the non-dysplastic tissue adjacent to advanced tumors (3.5 vs. 2, p=0.001). bcl-2 labelling index was significantly higher in the mucosa adjacent to advanced carcinomas (15 vs. 5, p=0.016) but this difference did not reach significance in the tumors (20 vs. 15, p=0.37). CONCLUSIONS: Our data indicate similar cell turnover during tumorigenesis of early and advanced cancer. p53 and bcl-2 protein accumulation is more intense in gastric mucosa adjacent to advanced tumors and p53 immunoreactivity peaks in advanced carcinomas.

Long-term therapy with adefovir dipivoxil in hepatitis B e antigen-negative patients developing resistance to lamivudine.

BACKGROUND: The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation. AIM: To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants. METHODS: Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy. RESULTS: The median follow-up after adefovir's onset was 31 (18-40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <10(4) copies/mL (P > 0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively (P > 0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy (P = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months. CONCLUSION: In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.

The role of NSAIDs in colon cancer prevention.

Experiments in animals and population-based studies have shown the efficacy of nonsteroidal antiinflammatory drugs in colorectal cancer prevention. COX-2 is overexpressed in dysplastic and neoplastic epithelium. COX-2 is a key-enzyme in several tumorigenic pathways, such as promotion of tumor angiogenesis. Non-selective inhibition of COX enzyme demonstrates a protective effect as well, suggesting that more than one mechanism takes place in neoplastic transformation. Blockade of COX enzyme by NSAIDs down-regulates its metabolic product prostaglandin E2. Inhibition of PGE2 seems to have a negative effect in cancer occurrence. Induction of apoptosis is another mechanism that explains the protective effect of NSAIDs. The recently discovered PPARdelta factor, is also overexpressed in neoplastic tissue, and may be a mediator through which COX-2 exerts its oncogenic effect.

Clinical trial: The effect of somatostatin vs. octreotide in preventing post-endoscopic increase in hepatic venous pressure gradient in cirrhotics with bleeding varices.

BACKGROUND: Hepatic venous pressure gradient (HVPG) increases significantly after endoscopic therapy in patients with bleeding oesophageal varices, which may precipitate further haemorrhage. Whether vasoactive drugs can suppress these changes remains unknown. AIM: To investigate the efficacy of somatostatin when compared with octreotide in preventing the post-endoscopic increase in HVPG during acute bleeding and whether the changes affect outcome. METHODS: Thirty-three cirrhotics with bleeding varices were randomized to receive somatostatin (n = 17) or octreotide (n = 16) under double-blind conditions, soon after their admission. HVPG measurements were performed before and immediately after endoscopic treatment. RESULTS: In the somatostatin group, postendotherapy HVPG values did not change significantly when compared with pre-treatment values (18.9 vs. 17.2, P = 0.092). Conversely, in the octreotide group, HVPG increased significantly after endoscopy (18.2 vs. 20.8, P = 0.003). The probability of 6-week survival without treatment failure was significantly higher in the somatostatin group (P = 0.024). Post-endoscopic HVPG value was independently associated with 6-week failure. CONCLUSIONS: Somatostatin, but not octreotide, effectively prevents the post-endoscopic increase in HVPG, which may be associated with low probability of treatment failure.

The Bcl-2/Bax system and apoptosis in ulcerative colitis.

BACKGROUND/AIMS: Ulcerative colitis (UC) constitutes a chronic inflammatory process of the colon of unknown etiology. Current data support a pivotal role of apoptosis in the evolution of pathogenesis of UC. We performed a prospective study in order to determine the role of Bcl-2, Bax and Bcl-x in the apoptotic pathway in UC. METHODOLOGY: We included 23 patients with UC and 11 controls. Histological severity of the disease was assessed according to the Sidney classification system. Patients in the UC group were divided in 2 groups according to histological severity of the disease. The TUNEL method was used for the in situ evaluation of apoptosis. Immunohistochemical staining was used for the detection of Bax, Bcl-2, Bcl-x. For the assessment of cellular proliferation we used the monoclonal antibody Ki67. Appropriate statistical methods were applied. RESULTS: Overall 77 specimens were assessed; 57 from UC patients and 20 from controls. Bcl-2, Bax and Bcl-x were upregulated in the group of patients with UC compared to controls. Nevertheless, Bax in epithelial cells and Bcl-x in lymphocytes were downregulated in patients with moderate/severe disease (p = 0.029 and 0.04 respectively). A weak correlation between epithelial apoptosis and Bcl-x expression in lymphocytes (r = 0.31, p = 0.02) was found. An even weaker correlation was also noticed between the epithelial component apoptosis and Bax in lymphocytes (r = 0.02, p = 0.07). CONCLUSIONS: Bcl-2/Bax system does not appear to be involved in the induction of apoptosis in UC. Activation of intraepithelial lymphocytes may be associated with epithelial apoptosis or simply represent epiphenomena related to the inflammatory process.

The puzzle of somatostatin: action, receptors, analogues and therapy.

The scientific search for the revelation of the multiple physiological aspects of somatostatin has already begun. Investigators have managed to clarify many pathophysiological processes that have been influenced or regulated by somatostatin. The focus of future research seems to be the therapeutic application of this accumulated knowledge. The aim of this study is to collect the available information on the action, receptors and use of somatostatin analogues in human tissues. For this reason findings were based on Internet search and complete studies with abstracts written in English. A special mention on the influence of somatostatin on the immune system and inflammatory bowel disease is also included.

Different aspects in functional dyspepsia.

Functional dyspepsia is still a puzzling medical problem. The causes are unknown, the pathogenetic mechanisms are uncertain, the management is controversial and medications are many times insufficient. The research so far has given conflicting results at all levels of investigation. This study represents an effort to collect all available data concerning the most disputed issues of functional dyspepsia. Topics regarding Helicobacter pylori eradication, pathophysiology, endoscopic and histologic correlations with symptomatology, the placebo effect and management options are presented following an evidence-based approach. Many articles, published in recent years, are discussed in order to obtain an overall insight of this peculiar symptom complex, named functional dyspepsia.

Prevalence and impact of upper and lower gastrointestinal symptoms in the Greek urban general population.

OBJECTIVES: To study the prevalence of gastrointestinal symptoms in the Greek urban general population, their associations with patient characteristics, and their effect on patients' daily activities. MATERIAL AND METHODS: The study included 700 adults from the Athens-Piraeus area selected by a 2-stage scheme based on the official maps of the Hellenic Statistic Service. Structured questionnaires were completed through personal interviews. Dyspepsia, gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS) were diagnosed according to widely accepted definitions. RESULTS: Of the 700 individuals, 53% reported > or = 1 gastrointestinal symptom during the past week and 55% during the past 6 months (dyspepsia: 48%, GERD: 38%, IBS: 21%). Only one disorder was diagnosed in 25% (dyspepsia: 18%, GERD: 7%), and > or = 2 disorders in 75% of symptomatic individuals. Dyspepsia or GERD was predominant in 7% and 16% and IBS in 28% and 19% of the patients with relevant symptoms during the past week and the past 6 months, respectively (p = 0.017). Substantial symptoms during the past 6 months were reported by 60% of the symptomatic individuals. Affected daily activities were reported by 22% of symptomatic and 5% of asymptomatic individuals (p < 0.001). CONCLUSIONS: Gastrointestinal symptoms are highly prevalent in the Greek urban general population and are substantial in the majority of symptomatic individuals. Dyspepsia and GERD are reported much more frequently than IBS symptoms, but there is a significant overlap between symptomatic diagnoses, while the predominant diagnosis may change over time. Gastrointestinal symptoms have a significant impact on patients' daily activities.

Genes and gastric cancer.

Gastric cancer remains quite a common malignancy and counts among the most important causes of cancer-related death worldwide. Although the pathogenesis is multifactorial, familial aggregation in a significant proportion of cases suggests the importance of genetic predisposition. The association between the E-cadherin/CDH1 gene germline mutations and the development of diffuse gastric cancer was the first evidence for a molecular basis of gastric cancer in predisposed families and led many authorities in the world to produce guidelines regarding the management of such families members. The recent advances in genetics resulted in the discovery of numerous genetic events occurring during the course of gastric carcinogenesis (activation of oncogenes, silencing of tumor suppressor genes, mutations in DNA-repairing genes) and contributed to a better understanding in pathogenesis. Many genetic changes described have been found to affect tumor's biological behavior. In this article the authors attempt a review of all the molecular alterations in gastric cancer described in the literature and their impact on the management of patients with an inherited predisposition to gastric cancer. The promising role of gene therapy in the treatment of gastric cancer in the near future is also commented on.