Non-Invasive Markers for the Detection of Gastric Precancerous Conditions.

Gastric cancer (GC) is still one of the most prevalent cancers worldwide, with a high mortality rate, despite improvements in diagnostic and therapeutic strategies. To diminish the GC burden, a modification of the current diagnostic paradigm, and especially endoscopic diagnosis of symptomatic individuals, is necessary. In this review article, we present a broad review and the current knowledge status on serum biomarkers, including pepsinogens, gastrin, Gastropanel®, autoantibodies, and novel biomarkers, allowing us to estimate the risk of gastric precancerous conditions (GPC)-atrophic gastritis and gastric intestinal metaplasia. The aim of the article is to emphasize the role of non-invasive testing in GC prevention. This comprehensive review describes the pathophysiological background of investigated biomarkers, their status and performance based on available data, as well as their clinical applicability. We point out future perspectives of non-invasive testing and possible new biomarkers opportunities.

Iron and Vitamin B12 Deficiency in Patients with Autoimmune Gastritis and Helicobacter pylori Gastritis: Results from a Prospective Multicenter Study.

INTRODUCTION: Iron and vitamin B12 deficiencies are common in patients with atrophic gastritis, but there are limited data on the prevalence of these deficiencies in different types of atrophic gastritis. METHODS: This multicenter, prospective study assessed micronutrient concentrations in histologically confirmed autoimmune gastritis (AIG, n = 45), Helicobacter pylori-related non-autoimmune gastritis (NAIG, n = 109), and control patients (n = 201). A multivariate analysis was performed to determine factors influencing those deficiencies. RESULTS: The median vitamin B12 concentration was significantly lower in AIG (367.5 pg/mL, Q1, Q3: 235.5, 524.5) than in NAIG (445.0 pg/mL, Q1, Q3: 355.0, 565.0, p = 0.001) and control patients (391.0 pg/mL, Q1, Q3: 323.5, 488.7, p = 0.001). Vitamin B12 deficiency was found in 13.3%, 1.5%, and 2.8% of AIG, NAIG, and control patients, respectively. Similarly, the median ferritin concentration was significantly lower in AIG (39.5 ng/mL, Q1, Q3: 15.4, 98.3 ng/mL) than in NAIG (80.5 ng/mL, Q1, Q3: 43.6, 133.9, p = 0.04) and control patients (66.5 ng/mL, Q1, Q3: 33.4, 119.8, p = 0.007). Iron deficiency and iron deficiency adjusted to CRP were present in 28.9% and 33.3% of AIG, 12.8% and 16.5% of NAIG, and 12.9% and 18.4% of controls, respectively. Multivariate analysis demonstrated that AIG patients had a higher risk of developing vitamin B12 deficiency (OR: 11.52 [2.85-57.64, p = 0.001]) and iron deficiency (OR: 2.92 [1.32-6.30, p = 0.007]) compared to control patients. Factors like age, sex, and H. pylori status did not affect the occurrence of vitamin B12 or iron deficiency. CONCLUSION: Iron and vitamin B12 deficiencies are more commonly observed in patients with AIG than in those with NAIG or control patients. Therefore, it is essential to screen for both iron and vitamin B12 deficiencies in AIG patients and include the treatment of micronutrient deficiencies in the management of atrophic gastritis patients.

Clinical Management of Patients with Gastric MALT Lymphoma: A Gastroenterologist's Point of View.

Gastric mucosa-associated lymphoid tissue (MALT) lymphomas (GML) are non-Hodgkin lymphomas arising from the marginal zone of the lymphoid tissue of the stomach. They are usually induced by chronic infection with Helicobacter pylori (H. pylori); however, H. pylori-negative GML is of increasing incidence. The diagnosis of GML is based on histological examination of gastric biopsies, but the role of upper endoscopy is crucial since it is the first step in the diagnostic process and, with currently available novel endoscopic techniques, may even allow an in vivo diagnosis of GML per se. The treatment of GML, which is usually localized, always includes the eradication of H. pylori, which should be performed even in H. pylori-negative GML. In the case of GML persistence after eradication of the bacteria, low-dose radiotherapy may be proposed, while systemic treatments (immunochemotherapy) should be reserved for very rare disseminated cases. In GML patients, at diagnosis but even after complete remission, special attention must be paid to an increased risk of gastric adenocarcinoma, especially in the presence of associated gastric precancerous lesions (gastric atrophy and gastric intestinal metaplasia), which requires adequate endoscopic surveillance of these patients.

Atrophic Gastritis and Autoimmunity: Results from a Prospective, Multicenter Study.

Despite a global decrease, gastric cancer (GC) incidence appears to be increasing recently in young, particularly female, patients. The causal mechanism for this "new" type of GC is unknown, but a role for autoimmunity is suggested. A cascade of gastric precancerous lesions, beginning with chronic atrophic gastritis (CAG), precedes GC. To test the possible existence of autoimmunity in patients with CAG, we aimed to analyze the prevalence of several autoantibodies in patients with CAG as compared to control patients. Sera of 355 patients included in our previous prospective, multicenter study were tested for 19 autoantibodies (anti-nuclear antibodies, ANA, anti-parietal cell antibody, APCA, anti-intrinsic factor antibody, AIFA, and 16 myositis-associated antibodies). The results were compared between CAG patients (n = 154), including autoimmune gastritis patients (AIG, n = 45), non-autoimmune gastritis patients (NAIG, n = 109), and control patients (n = 201). ANA positivity was significantly higher in AIG than in NAIG or control patients (46.7%, 29%, and 27%, respectively, p = 0.04). Female gender was positively associated with ANA positivity (OR 0.51 (0.31-0.81), p = 0.005), while age and H. pylori infection status were not. Myositis-associated antibodies were found in 8.9% of AIG, 5.5% of NAIG, and 4.4% of control patients, without significant differences among the groups (p = 0.8). Higher APCA and AIFA positivity was confirmed in AIG, and was not associated with H. pylori infection, age, or gender in the multivariate analysis. ANA antibodies are significantly more prevalent in AIG than in control patients, but the clinical significance of this finding remains to be established. H. pylori infection does not affect autoantibody seropositivity (ANA, APCA, AIFA). The positivity of myositis-associated antibodies is not increased in patients with CAG as compared to control patients. Overall, our results do not support an overrepresentation of common autoantibodies in patients with CAG.

Serum pepsinogens can help to discriminate between H. pylori-induced and auto-immune atrophic gastritis: Results from a prospective multicenter study.

BACKGROUND: Serum pepsinogen (PG) testing is recommended by the European guidelines for diagnosis of chronic atrophic gastritis (CAG). However, wide variations in diagnostic performances are observed, due to the differences in the extent of gastric atrophy, and possibly in its origin (Helicobacter pylori-, autoimmune (AIG)). AIM: To analyze the diagnostic performances of PGs testing according to these different parameters, using enzyme-linked-immunosorbent serologic assay (ELISA) and chemiluminescent immunoassay (CLEIA). METHODS: Serum samples from patients having undergone gastroscopy with biopsies in five French centers were collected prospectively. Sensitivity (Se), specificity (Sp), and Area Under Curve were analyzed according to the extent and origin of CAG. RESULTS: Overall, 344 patients (156 males [45%]; mean age 58.8 [±14.2] years) were included, among whom 44 had AIG. Diagnostic performances of PG I for the detection of corpus CAG were excellent, with Se and Sp of 92.7% and 99.1% for ELISA and 90.5% and 98.2% for CLEIA, respectively. For AIG, corresponding values were 97.7% and 97.4% for ELISA, and 95.6% and 97.1% for CLEIA. In multivariate analysis, PG levels were associated with the auto-immune origin (p<0.001) but not with the extent of the atrophic gastritis. CONCLUSIONS: Pepsinogens are highly efficient for the diagnosis of corpus-limited CAG and allow to discriminate AIG from H. pylori-induced gastritis.

Role of the endoscopic Doppler probe in nonvariceal upper gastrointestinal bleeding: Systematic review and meta-analysis.

OBJECTIVES: The effectiveness of the Doppler endoscopic probe (DEP) remains unclear in nonvariceal upper gastrointestinal bleeding (NVUGIB). We thus performed a systematic review characterizing the effectiveness of DEP in patients with NVUGIB addressing this question. METHODS: A literature search was done until July 2021 using MEDLINE, EMBASE, and ISI Web of Science. A series of meta-analyses were performed assessing outcomes among observational and interventional studies for DEP signal positive and negative lesions as well as DEP-assisted versus standard endoscopies. The primary outcome was "overall rebleeding"; secondary outcomes included all-cause mortality, bleeding-related mortality, need for surgery, length of stay, intensive care unit stay, and angiography. RESULTS: Fourteen studies were included from 1911 citations identified. Observational studies compared bleeding lesions with DEP-positive versus DEP-negative signals (11 studies, n = 800 prehemostasis; five studies, n = 148 with posthemostasis data). Three interventional studies (n = 308) compared DEP-assisted to standard endoscopy management. DEP signal positive versus negative lesions either prior to or following any possible hemostasis were at greater risk of overall rebleeding (odds ratio [OR] 6.54 [2.36, 18.11] and OR 25.96 [6.74, 100.0], respectively). The use of DEP during upper endoscopy significantly reduced overall rebleeding rates (OR 0.27 [0.14, 0.54]). When removing outcomes analysis for which only one study was available, all evaluable outcomes were improved with DEP characterization of management guidance except for all-cause mortality. CONCLUSION: Although with low certainty evidence, DEP-related information improves on sole visual prediction of rebleeding in NVUGIB, with DEP-guided management yielding decreased overall rebleeding, bleeding-related mortality, and need for surgery.

Single-cell profiling to transform immunotherapy usage and target discovery in immune-mediated inflammatory diseases.

Immunotherapy drugs are transforming the clinical care landscape of major human diseases from cancer, to inflammatory diseases, cardiovascular diseases, neurodegenerative diseases and even aging. In polygenic immune-mediated inflammatory diseases (IMIDs), the clinical benefits of immunotherapy have nevertheless remained limited to a subset of patients. Yet the identification of new actionable molecular candidates has remained challenging, and the use of standard of care imaging and/or histological diagnostic assays has failed to stratify potential responders from non-responders to biotherapies already available. We argue that these limitations partly stem from a poor understanding of disease pathophysiology and insufficient characterization of the roles assumed by candidate targets during disease initiation, progression and treatment. By transforming the resolution and scale of tissue cell mapping, high-resolution profiling strategies offer unprecedented opportunities to the understanding of immunopathogenic events in human IMID lesions. Here we discuss the potential for single-cell technologies to reveal relevant pathogenic cellular programs in IMIDs and to enhance patient stratification to guide biotherapy eligibility and clinical trial design.

Adhesion of Gastric Cancer Cells to the Enteric Nervous System: Comparison between the Intestinal Type and Diffuse Type of Gastric Cancer.

Background: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. The enteric nervous system (ENS) has been suggested to be involved in cancer development and spread. Objective: To analyze the GC cell adhesion to the ENS in a model of co-culture of gastric ENS with GC cells. Methods: Primary culture of gastric ENS (pcgENS), derived from a rat embryo stomach, was developed. The adhesion of GC cells to pcgENS was studied using a co-culture model. The role of N-Cadherin, a cell-adhesion protein, was evaluated. Results: Compared to intestinal-type GC cells, the diffuse-type GC cancer cells showed higher adhesion to pcgENS (55.9% ± 1.075 vs. 38.9% ± 0.6611, respectively, p < 0.001). The number of diffuse-type GC cells adherent to pcgENS was significantly lower in neuron-free pcgENS compared to neuron-containing pcgENS (p = 0.0261 and 0.0329 for AGS and MKN45, respectively). Confocal microscopy showed that GC cells adhere preferentially to the neurons of the pcgENS. N-Cadherin blockage resulted in significantly decreased adhesion of the GC cells to the pcgENS (p < 0.01). Conclusion: These results suggest a potential role of enteric neurons in the dissemination of GC cells, especially of the diffuse-type, partly through N-Cadherin.

Review article: obesity and colorectal cancer.

BACKGROUND: Obesity is a growing global public health problem. More than half the European and North American population is overweight or obese. Colon and rectum cancers are still the second leading cause of cancer death worldwide, and epidemiological data support an association between obesity and colorectal cancers (CRCs). AIM: To review the literature on CRC epidemiology in obese subjects, assessing the effects of obesity, including childhood or maternal obesity, on CRC, diagnosis, management, and prognosis, and discussing targeted prophylactic measures. METHOD: We searched PubMed for obesity/overweight/metabolic syndrome and CRC. Other key words included 'staging', 'screening', 'treatment', 'weight loss', 'bariatric surgery' and 'chemotherapy'. RESULTS: In Europe, about 11% of CRCs are attributed to overweight and obesity. Epidemiological data suggest that obesity is associated with a 30%-70% increased risk of colon cancer in men, the association being less consistent in women. Visceral fat or abdominal obesity seems to be of greater concern than subcutaneous fat obesity, and any 1 kg/m2 increase in body mass index confers more risk (hazard ratio 1.03). Obesity might increase the likelihood of recurrence or mortality of the primary cancer and may affect initial management, including accurate staging. The risk maybe confounded by different factors, including lower adherence to organised CRC screening programmes. It is unclear whether bariatric surgery helps reduce rectal cancer risk. CONCLUSIONS: Despite a growing body of evidence linking obesity to CRC, many questions remain unanswered, including whether we should screen patients with obesity earlier or propose prophylactic bariatric surgery for certain patients with obesity.

Primary Gastrointestinal Follicular Lymphomas: A Prospective Study of 31 Patients with Long-term Follow-up Registered in the French Gastrointestinal Lymphoma Study Group (GELD) of the French Federation of Digestive Oncology (FFCD).

BACKGROUND/AIMS: Primary gastrointestinal follicular lymphomas (PGFL) are very rare. Our aim was to analyze the clinical features, management, and long-term outcomes in a prospective series of patients diagnosed with PGFL. METHODS: All adult patients with PGFL, consecutively enrolled into the multicenter French study between 1990 and 2017, were evaluated and followed up prospectively after undergoing a complete work-up. Clinical, pathological and endoscopic features, as well as treatment outcomes, were analyzed. RESULTS: Thirty-one patients (16 men, median age 62 years, range 33 to 79 years) with PGFL were included. The median follow-up was 92 months (range, 6 to 218 months). In the majority of patients (n=14), lymphoma was incidentally diagnosed during endoscopy. Otherwise, the most frequent circumstances of diagnosis were abdominal pain (n=7) and dyspepsia (n=5). The duodenum was the most common site of involvement (n=19) and multifocal localizations were seen in seven patients (22%). The most frequent first line strategy was surveillance applied in 22 patients (71%), of whom nine reached spontaneous, complete remission and 11 had stable disease. Seven patients (23%) received chemotherapy as first line treatment, and two underwent resection. Of seven patients who received chemotherapy, four achieved complete remission. In three patients, transformation into a high-grade lymphoma occurred. CONCLUSIONS: The diagnosis of PGFL is frequently fortuitous. The most common localization is in the duodenum. The disease has an indolent course and a good prognosis, however, rare cases of transformation into aggressive high-grade lymphoma may occur. An appropriate characterization and follow-up of these lymphomas is mandatory for their optimal management.

Serum Pepsinogens Combined with New Biomarkers Testing Using Chemiluminescent Enzyme Immunoassay for Non-Invasive Diagnosis of Atrophic Gastritis: A Prospective, Multicenter Study.

BACKGROUND: Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), a gastric precancerous lesion, is of growing interest for identification of patients at increased risk of gastric cancer. The aim was to analyze the diagnostic performance of serum pepsinogen testing using another method, chemiluminescent enzyme immunoassay (CLEIA), as well as of other new potential biomarkers. MATERIAL AND METHODS: The sera of patients considered at increased risk of gastric cancer and undergoing upper endoscopy collected in our previous prospective, multicenter study were tested for pepsinogen I (PGI) and II (PGII), interleukin-6 (IL-6), human epididymal protein 4 (HE-4), adiponectin, ferritin and Krebs von den Lungen (KL-6) using the CLEIA. The diagnostic performance for the detection of AG was calculated by taking histology as the reference. RESULTS: In total, 356 patients (162 men (46%); mean age 58.6 (±14.2) years), including 152 with AG, were included. For the detection of moderate to severe corpus AG, sensitivity and specificity of the pepsinogen I/II ratio were of 75.0% (95%CI 57.8-87.9) and 92.6% (88.2-95.8), respectively. For the detection of moderate to severe antrum AG, sensitivity of IL-6 was of 72.2% (95%CI 46.5-90.3). Combination of pepsinogen I/II ratio or HE-4 showed a sensitivity of 85.2% (95%CI 72.9-93.4) for the detection of moderate to severe AG at any location. CONCLUSION: This study shows that PG testing by CLEIA represents an accurate assay for the detection of corpus AG. Additionally, IL-6 and HE-4 may be of interest for the detection of antrum AG. MINI-ABSTRACT: Pepsinogens testing by chemiluminescent enzyme immunoassay is accurate for the detection of corpus atrophic gastritis. IL-6 and HE-4 maybe of interest for the detection of antrum atrophic gastritis.

Systematic upper endoscopy concomitant with colonoscopy performed within the colorectal cancer screening program: Impact on the patients' management.

BACKGROUND AND AIMS: The French colorectal cancer screening program is based on a fecal immunochemical test, followed by colonoscopy in case of positivity. The benefit of adding a concomitant upper endoscopy to detect upper digestive lesions (precancerous or others) is still debated. Our aim was to evaluate the frequency of upper digestive lesions detected by upper endoscopy performed concomitantly with colonoscopy following a positive fecal immunochemical test, and their impact on the patients' management (i.e., surveillance, medical treatment, endoscopic or surgical procedure). METHODS: Data of all the patients who consulted for a positive test between May 2016 and May 2019 in our center, and for whom concomitant upper endoscopy and colonoscopy were performed, were analyzed retrospectively. Patients with significant history of upper gastrointestinal diseases or with current gastrointestinal symptoms were excluded. RESULTS: One hundred patients were included [median age (min-max): 62 (50-75), men 64%]. Macroscopic and/or microscopic upper digestive lesions were found in 58 of them (58%): Helicobacter pylori infection in 17 patients, gastric precancerous lesions in 9 patients (chronic atrophic gastritis with intestinal metaplasia, n=8, low grade dysplasia, n=1), Barrett's esophagus requiring surveillance in 4 patients, and 1 duodenal adenoma with low-grade dysplasia. In 44 patients (44%), the upper endoscopy findings had an impact on patients' management, with no significant difference between the groups with positive (CRC or advanced adenoma)- or negative (any other lesions or normal) colonoscopy. CONCLUSION: A systematic upper endoscopy combined with colonoscopy for positive fecal immunochemical test could represent an efficient strategy for upper digestive lesions screening in France. Further studies are necessary to confirm these results and to evaluate cost-effectiveness of this approach.

The pharmacotherapeutic management of gastroesophageal reflux disease (GERD).

INTRODUCTION: Gastroesophageal reflux disease (GERD) is a very common worldwide condition, affecting about 15-20% of the whole population, and representing a major burden for health-care systems. Because of its frequency, health physicians - family doctors as well as specialists - should be aware of the different pharmacotherapeutic approaches in managing GERD, according to disease severity. AREAS COVERED: Authors summarize the pharmacological management of GERD in adults, present the different pharmaceutical classes, and review the evidence on efficacy for each treatment according to the most common clinical scenarios: non-erosive gastroesophageal reflux disease (NERD), erosive esophagitis (EE), and proton-pump inhibitor (PPI) refractory GERD. They also provide an overview of treatments under development. EXPERT OPINION: To date, PPIs remain the most effective treatment option for both NERD and EE. However, Potassium-Competitive Acid blockers (PCAB) may be considered, with at least similar efficacy in Asian populations. Preliminary data suggest that PCABs could be superior to classic PPIs in patients with severe EE, and may also be of particular interest in the management of PPI-refractory GERD patients. Their definitive role in GERD management, however, still remains to be determined based on properly designed and conducted randomized clinical trials.

Evaluation of a Phone Call Reminder Strategy in the Surveillance of Patients with Gastric Precancerous Lesions Lost to Follow-Up.

BACKGROUND: Surveillance of gastric precancerous lesions (GPL) may reduce gastric cancer (GC)-related mortality, but some patients with GPL are lost to follow-up. OBJECTIVE: The aim of this study was to evaluate the feasibility and efficacy of a "phone-call" strategy in surveillance of the lost to follow-up patients. PATIENTS AND METHODS: Among all the patients diagnosed with GPL (atrophic gastritis, intestinal metaplasia, low-grade dysplasia) between 2000 and 2015, we identified those who should undergo surveillance endoscopy according to the current guidelines. They were contacted by telephone and invited to undergo endoscopy with gastric biopsies for histological analysis. RESULTS: Among 535 patients with GPL, 134 were contacted. Sixty-two (46%) could not be joined, 36 did not have endoscopy for other reasons, and finally, 36 patients (22 males, median age 65 years) were included. After the median time interval of 57 months between 2 endoscopies, 18 patients showed stability, 11 regression, and 7 progression of GPL, including 1 patient who developed GC. CONCLUSION: Despite several telephone calls, only one-third of the contacted patients could be brought to surveillance endoscopy. Most of the patients showed stability of GPL, but 1 progressed to GC and could be successfully treated.

Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population.

Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. Its development is a multistep process that spans more than 15 years, thereby providing an opportunity for prevention and early detection. The high incidence and mortality rates emphasise the need for prevention and screening. Many countries have therefore introduced CRC screening programmes. It is expected, and preliminary evidence in some countries suggests, that this screening effort will decrease CRC-related mortality rates. CRC prevention involves a healthy lifestyle and chemoprevention-more specifically, oral chemoprevention that can interfere with progression from a normal colonic mucosa to adenocarcinoma. This preventive effect is important for individuals with a genetic predisposition, but also in the general population. The ideal chemopreventive agent, or combination of agents, remains unknown, especially when considering safety during long-term use. This review evaluates the evidence across 80 meta-analyses of interventional and observational studies of CRC prevention using medications, vitamins, supplements and dietary factors. This review suggests that the following factors are associated with a decreased incidence of CRC: aspirin, non-steroidal anti-inflammatory drugs, magnesium, folate, a high consumption of fruits and vegetables, fibre and dairy products. An increased incidence of CRC was observed with frequent alcohol or meat consumption. No evidence of a protective effect for tea, coffee, garlic, fish and soy products was found. The level of evidence is moderate for aspirin, ß-carotene and selenium, but is low or very low for all other exposures or interventions.

A panel of stomach-specific biomarkers (GastroPanel®) for the diagnosis of atrophic gastritis: A prospective, multicenter study in a low gastric cancer incidence area.

BACKGROUND: Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), considered as gastric precancerous lesion, is of growing interest and recommended by current guidelines. Our aim was to evaluate the diagnostic performance of a panel of biomarkers (GastroPanel®) for the detection of AG in France, a country of a low gastric cancer (GC) incidence. MATERIAL AND METHODS: In this prospective, multicenter, cross-sectional study, consecutive patients considered at increased risk of GC and undergoing upper endoscopy with gastric biopsies were included. Blood samples were collected for the analysis of GastroPanel® (association of Pepsinogens I and II, Gastrin-17, and Helicobacter pylori serology) using ELISA. The results of GastroPanel® were compared to the results of histology considered as the reference. RESULTS: Between 2016 and 2019, 344 patients (148 cases with AG, 196 controls without AG) were included. Sensitivity, specificity, positive, and negative predictive values for the detection of AG by GastroPanel® were of 39.9% (95% CI 31.9; 48.2), 93.4% (95% CI 88.9; 96.4), 81.9 (95% CI 71.1; 90.0), and 67.3 (95% CI 61.4; 72.8), respectively. The sensitivity was significantly higher for the detection of severe AG [60.8% (95% CI 46.1; 74.6) P = .015] and corpus AG [61.0% (95% CI 49.2; 72.0), P = .004]. Diagnostic performances of GastroPanel® tended to be better than those of Pepsinogen I alone, but the difference did not reach statistical significance (P = .068). CONCLUSION: Serum pepsinogen and GastroPanel® tests show promising results for the detection of AG, especially of corpus AG and severe AG, in patients at high risk of GC in France.

Gastric Cancer: Where Are We Heading?

BACKGROUND: Despite its decreasing incidence, gastric cancer (GC) remains one of the leading cancers in the world and an important global healthcare problem due to its overall high prevalence and high mortality rate. SUMMARY: GC is a consequence of Helicobacter pylori infection in 90% of cases, while in 10% Epstein Barr Virus may be responsible. Moreover, some recent epidemiological data suggest an increasing incidence in some young patients groups possibly due to autoimmunity, and if this tendency is confirmed, it may change the epidemiology of GC in the future. The pathogenesis of GC is mainly related to H. pylori infection, but recent data indicate the possible role of other bacteria and their metabolites, like N-nitrosocompounds or acetaldehyde, interfering during the last steps of carcinogenesis. The new molecular classifications of GCs show a great heterogeneity of this neoplasia, which may in the future help to define personalized treatment strategies for the patients. Early detection and proper surveillance of high risk patients should be our major objectives. Key Messages: GC is still an important healthcare problem, with its several aspects which remain the major challenges for the future.