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.

Role of compliance in Helicobacter pylori eradication treatment: Results of the European Registry on H. pylori management.

BACKGROUND: Adherence to Helicobacter pylori (H. pylori) eradication treatment is a cornerstone for achieving adequate treatment efficacy. OBJECTIVE: To determine which factors influence compliance with treatment. METHODS: A systematic prospective non-interventional registry (Hp-EuReg) of the clinical practice of European gastroenterologists. Compliance was considered adequate if ≥90% drug intake. Data were collected until September 2021 using the AEG-REDCap e-CRF and were subjected to quality control. Modified intention-to-treat analyses were performed. Multivariate analysis carried out the factors associated with the effectiveness of treatment and compliance. RESULTS: Compliance was inadequate in 646 (1.7%) of 38,698 patients. The non-compliance rate was higher in patients prescribed longer regimens (10-, 14-days) and rescue treatments, patients with uninvestigated dyspepsia/functional dyspepsia, and patients reporting adverse effects. Prevalence of non-adherence was lower for first-line treatment than for rescue treatment (1.5% vs. 2.2%; p < 0.001). Differences in non-adherence in the three most frequent first-line treatments were shown: 1.1% with proton pump inhibitor + clarithromycin + amoxicillin; 2.3% with proton pump inhibitor clarithromycin amoxicillin metronidazole; and 1.8% with bismuth quadruple therapy. These treatments were significantly more effective in compliant than in non-compliant patients: 86% versus 44%, 90% versus 71%, and 93% versus 64%, respectively (p < 0.001). In the multivariate analysis, the variable most significantly associated with higher effectiveness was adequate compliance (odds ratio, 6.3 [95%CI, 5.2-7.7]; p < 0.001). CONCLUSIONS: Compliance with Helicobacter pylori eradication treatment is very good. Factors associated with poor compliance include uninvestigated/functional dyspepsia, rescue-treatment, prolonged treatment regimens, the presence of adverse events, and the use of non-bismuth sequential and concomitant treatment. Adequate treatment compliance was the variable most closely associated with successful eradication.

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.

Comparison of the management of Helicobacter pylori infection between the older and younger European populations.

The prevalence of Helicobacter pylori remains high in the older population. Specific age-related peculiarities may impact the outcomes of H. pylori treatment. The aim of the study was to evaluate the diagnostics and effectiveness of H. pylori eradication between the younger and older European populations. "European Registry on H. pylori Management (Hp-EuReg)" data from 2013 to 2022 were analyzed. Patients were divided into older (≥ 60 years) and younger (18-59 years) groups. Modified intention-to-treat (mITT) and per-protocol (PP) analysis was performed. 49,461 patients included of which 14,467 (29%) were older-aged. Concomitant medications and penicillin allergy were more frequent among the older patients. Differences between younger and older populations were observed in treatment duration in first-line treatment and in proton pump inhibitors (PPIs) doses in second-line treatment. The overall incidence of adverse events was lower in the older adults group. The overall first-line treatment mITT effectiveness was 88% in younger and 90% in the older patients (p < 0.05). The overall second-line mITT treatment effectiveness was 84% in both groups. The effectiveness of the most frequent first- and second-line triple therapies was suboptimal (< 90%) in both groups. Optimal efficacy (≥ 90%) was achieved by using bismuth and non-bismuth-based quadruple therapies. In conclusion, the approach to the diagnostics and treatment of H. pylori infection did not generally differ between younger and older patients. Main differences were reported in the concurrent medications, allergy to penicillin and adverse events both in first- and second-line treatment. Optimal effectiveness rates were mostly achieved by using bismuth and non-bismuth-based quadruple therapies. No clinically relevant differences in the effectiveness between the age groups were observed.

Analysis of Clinical Phenotypes through Machine Learning of First-Line H. pylori Treatment in Europe during the Period 2013-2022: Data from the European Registry on H. pylori Management (Hp-EuReg).

The segmentation of patients into homogeneous groups could help to improve eradication therapy effectiveness. Our aim was to determine the most important treatment strategies used in Europe, to evaluate first-line treatment effectiveness according to year and country. Data collection: All first-line empirical treatments registered at AEGREDCap in the European Registry on Helicobacter pylori management (Hp-EuReg) from June 2013 to November 2022. A Boruta method determined the "most important" variables related to treatment effectiveness. Data clustering was performed through multi-correspondence analysis of the resulting six most important variables for every year in the 2013-2022 period. Based on 35,852 patients, the average overall treatment effectiveness increased from 87% in 2013 to 93% in 2022. The lowest effectiveness (80%) was obtained in 2016 in cluster #3 encompassing Slovenia, Lithuania, Latvia, and Russia, treated with 7-day triple therapy with amoxicillin-clarithromycin (92% of cases). The highest effectiveness (95%) was achieved in 2022, mostly in Spain (81%), with the bismuth-quadruple therapy, including the single-capsule (64%) and the concomitant treatment with clarithromycin-amoxicillin-metronidazole/tinidazole (34%) with 10 (69%) and 14 (32%) days. Cluster analysis allowed for the identification of patients in homogeneous treatment groups assessing the effectiveness of different first-line treatments depending on therapy scheme, adherence, country, and prescription year.

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.

Clinical Management of Gastric Cancer Treatment Regimens.

Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer-associated death in the world. Endoscopic resection can be the treatment in selected cases of very early gastric cancer. Surgery is recommended for tumors that do not meet the criteria for endoscopic resection or for tumors with lymph node invasion but without distant metastases. Gastrectomy should include D2 lymphadenectomy without splenectomy. Perioperative or adjuvant chemotherapy improves survival and is recommended in locally advanced gastric cancer (>T1 and/or with lymph nodes positive). In locally advanced cancer with microsatellite instability (MSI), immunotherapy should be considered. Advanced unresectable or metastatic gastric cancer has a poor prognosis. The basis of the treatment is cytotoxic chemotherapy, with platinum and fluoropyrimidine doublet in the first line. Targeted therapies can be combined with chemotherapy. Trastuzumab (anti-HER2) is recommended in the first line in HER2-positive cancer. Ramucirumab (anti-VEGFR2) is recommended in the second line, in addition to paclitaxel chemotherapy. Zolbetuximab (anti-Claudine 18.2) should also be considered in the first line in Claudine 18.2-positive cancer. Immunotherapy can also be associated with chemotherapy in the first line of PD-L1-positive cancer. In HER2-positive and PD-L1-positive cancer, adjunction of trastuzumab and immunotherapy should be considered. In advanced and metastatic cancer with microsatellite instability (MSI), immunotherapy should be the first choice depending on its availability. Important progress has been made in recent years in the treatment of gastric cancer, especially due to a better understanding of molecular characteristics and heterogeneity of this disease. New targets and therapeutic approaches are being developed, which will very likely lead to changes in the management of gastric cancer.

Prolonged response on olaparib maintenance in metastatic pancreatic acinar cell carcinoma associated with a germline BRCA 2 mutation, revealed by severe panniculitis.

This 38-year-old man has a familial BRCA2 mutation. He presented with skin erythema, polyarthritis, dactylitis, and febrile erythema nodosum; a biopsy of a liver metastase revealed acinar cell carcinoma of the pancreas. After FOLFIRINOX, olaparib was initiated, and 24 months after, the patient was PS 0 and asymptomatic.

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.

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.

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.

[Re-visiting the Pronopall score ten years later: A multicenter retrospective study]. / Réévaluation du score Pronopall : une étude rétrospective multicentrique.

INTRODUCTION: The Pronopall score, which distinguishes 3 prognostic groups in patients with advanced cancer, was initially proposed in 2008 and validated in a study published in 2018 but including patients between 2009 and 2010. Since the last decade, cancer management and therapeutic options have progressed. The objective of this study was to confirm the value of this score in patients with digestive and thoracic cancer. METHODS: From July 2019 to November 2020, this retrospective multi-center study included patients with digestive or thoracic cancers who fulfilled the same inclusion criteria as those used in the initial study, and in whom the Pronopall score could be calculated using its four variables (albumin serum level, LDH level, ECOG score, number of metastatic sites). Survival curves were analyzed using the Kaplan-Meier method. RESULTS: One hundred patients were included. According to the Pronopall score, patients were separated into group A (score 8-10, 7 patients), group B (score 4-7, 41 patients) and group C (score 0-3, 52 patients). Median overall survival was 73 days, CI [17-129], 228 days, CI [128-328] and 575 days, CI [432-718] for groups A, B and C, respectively. Survival at 2 months was 28 % for population A, 61 % for population B, and 94 % for population C. CONCLUSION: This study confirms that the Pronopall score still allows clinically relevant discrimination of patients, score C being associated with a good prognosis compared to scores A and B.

Cancer Induces a Stress Ileopathy Depending on ß-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis.

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of ß-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. SIGNIFICANCE: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a ß-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873.