Magenkarzinom: Kombination aus Zolbetuximab und Chemotherapie bietet neuen therapeutischen Ansatz

<b>Background:</b> Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. <b>Patients and methods:</b> The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m² then 600 mg/m² Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m² Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. <b>Results:</b> In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29–0.67; P &#x3c; 0.0005] and OS (HR = 0.55; 95% CI, 0.39–0.77; P &#x3c; 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23–0.62; P &#x3c; 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39–0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1–2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). <b>Conclusions:</b> In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m² is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

A Deep Learning Convolutional Neural Network Can Differentiate Between Helicobacter Pylori Gastritis and Autoimmune Gastritis With Results Comparable to Gastrointestinal Pathologists

Context.— Pathology studies using convolutional neural networks (CNNs) have focused on neoplasms, while studies in inflammatory pathology are rare. We previously demonstrated a CNN differentiates reactive gastropathy, Helicobacter pylori gastritis (HPG), and normal gastric mucosa. Objective.— To determine whether a CNN can differentiate the following 2 gastric inflammatory patterns: autoimmune gastritis (AG) and HPG. Design.— Gold standard diagnoses were blindly established by 2 gastrointestinal (GI) pathologists. One hundred eighty-seven cases were scanned for analysis by HALO-AI. All levels and tissue fragments per slide were included for analysis. The cases were randomized, 112 (60%; 60 HPG, 52 AG) in the training set and 75 (40%; 40 HPG, 35 AG) in the test set. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The test set was blindly reviewed by pathologists with different levels of GI pathology expertise as follows: 2 GI pathologists, 2 general surgical pathologists, and 2 residents. Each pathologist rendered their preferred diagnosis, HPG or AG. Results.— At the HALO-AI AD percentage cutoff of 50% or more, the CNN results were 100% concordant with the gold standard diagnoses. On average, autoimmune gastritis cases had 84.7% HALO-AI autoimmune gastritis AD and HP cases had 87.3% HALO-AI HP AD. The GI pathologists, general anatomic pathologists, and residents were on average, 100%, 86%, and 57% concordant with the gold standard diagnoses, respectively. Conclusions.— A CNN can distinguish between cases of HPG and autoimmune gastritis with accuracy equal to GI pathologists.

Amoxicillin secretion by gastric mucosa in Chernobyl nuclear power plant accident recovery workers with atrophic and nonatrophic gastritis undergoing eradication therapy

Relevance. Today gastric cancer is still one of the oncologic diseases most often leading to death. H. pylori eradication reduces risk of gastric cancer, but its efficacy depends on gastric mucosa state. Atrophy of gastric mucosa is more common in Chernobyl nuclear power plant (CNPP) accident recovery workers than in patients who have not been involved in CNPP accident recovery works. It seems especially important to investigate the features of antibiotics transport to H. pylori colonization area in this contingent.Intention – to determine the features of amoxicillin secretion by gastric mucosa in CNPP accident recovery workers with atrophic and nonatrophic gastritis undergoing H. pylori eradication.Methodology. 65 CNPP accident recovery workers were divided into groups depending on state of gastric mucosa according to endoscopic and histological examination, immunosorbent assay of pepsinogens I and II and gastrin-17 basal serum levels. On the first day of eradication therapy, gastric secretion samples were obtained via nasogastric probe 30, 60, 120, 180 and 240 minutes after oral amoxicillin administration. Drug concentrations in gastric secretion were assessed via liquid chromatography-mass spectrometry.Results and discussion. Amoxicillin concentrations in gastric secretion samples were lower (р < 0.01) in patients with atrophic antral gastritis than in patients with normal gastric mucosa and atrophic fundal gastritis. Patients with fundal atrophy were characterized by lower amoxicillin concentrations 30 and 60 (p = 0.02) minutes after drug intake than in patients with normal gastric mucosa, and higher concentration in the 120th (p < 0.01) and 180th (p = 0.02) minute than in patients with antral atrophy. Amoxicillin concentrations in patients with antral atrophy were lower (p < 0.01) than in non-atrophy group in the 30th, 60th and 120th minute. In the 240th minute, amoxicillin concentrations in patients with fundal atrophy exceeded concentrations in both other groups (p < 0.01). Amoxicillin concentration peak was registered in patients with fundal and antral atrophy in the 180th minute, in patients without atrophy – from the 30th to 120th minute.Conclusion. Atrophy of gastric mucosa is characterized by decreased transport of orally administered amoxicillin from bloodstream to gastric lumen. Depending on gastric mucosa state, amoxicillin concentrations in gastric secretion should be evaluated at different time points after drug administration: in patients with atrophic gastritis – in the 180th minute, in patients without atrophy – in the 120th minute. While predicting the efficacy and choosing H. pylori eradication regimen, morphological and functional state of gastric mucosa should be taken into account.

Helicobacter pylori and Epstein–Barr Virus Infection in Gastric Diseases: Correlation with IL-10 and IL1RN Polymorphism

Introduction. Helicobacter pylori and Epstein–Barr virus (EBV) infection have recently been shown to be associated with gastric diseases. Polymorphisms in genes encoding cytokines such as interleukin 10 (IL-10) and interleukin 1 Receptor (IL-1RN) influence cytokine secretion levels and appear to contribute to the risk of developing gastroduodenal diseases. To our knowledge, this is the first preliminary study to address the association of coinfection with H. pylori and EBV and their correlation with genetic predisposition in the development of gastric diseases. Methods. Gastric biopsy samples of 96 patients with different gastric diseases were used. Results. Our results showed that the rate of coinfection was higher in patients with gastric cancer than in patients with normal gastric mucosa, active chronic gastritis, and MALT lymphoma. As regards the characterization of H. pilory strains, the polymorphism s1m1i1 of vacA gene was more frequent in patients with MALT Lymphoma in comparison to others, while the polymorphism s2m2i2 was most frequent in patients with normal gastric mucosa. In addition, patients who tested positive for the cagA gene were more frequently those affected with gastric cancer than those with inactive chronic gastritis. Similarly, the patients with oipA gene ON were more frequently those with gastric cancer than those with inactive chronic gastritis. Conclusion. According to our analysis, there was no correlation between coinfection and polymorphisms in genes encoding IL-10 and IL-1RN. We conclude that various factors can be involved in the development of gastric diseases.

NT5E is associated with unfavorable prognosis and regulates cell proliferation and motility in gastric cancer

Ecto-5′-nucleotidase (NT5E) is a glycosylphosphatidylinositol anchored cell surface protein, and has been suggested to be dysregulated in most types of human cancer including gastric cancer. The aim of the present study was to present more evidence about the clinical and prognostic value of Ecto-5′-nucleotidase in gastric cancer patients, and preliminarily explore the biological function of Ecto-5′-nucleotidase in gastric cancer cells. In our study, high Ecto-5′-nucleotidase expression was observed in gastric cancer tissues and cell lines, respectively, compared with normal gastric mucosa tissues cells. Meanwhile, TCGA database also indicated that Ecto-5′-nucleotidase expression levels were notably elevated in gastric cancer tissues compared with normal gastric mucosa tissues. Furthermore, high-expression of Ecto-5′-nucleotidase was obviously associated with advanced clinical stage, deep tumor invasion, lymph node metastasis and distant metastasis in gastric cancer patients. The survival analyses of TCGA database and our study consistent suggested high Ecto-5′-nucleotidase expression was negatively correlated with overall survival time in gastric cancer patients. The univariate and multivariate Cox proportional hazards regression model showed high Ecto-5′-nucleotidase expression was an independent poor prognostic factor for gastric cancer patients. Moreover, silencing of Ecto-5′-nucleotidase expression suppressed cell proliferation, migration and invasion in vitro in gastric cancer. In conclusion, Ecto-5′-nucleotidase is a credible prognostic biomarker, and serves as a potential therapeutic target in gastric cancer.

Expression of MUC5AC in normal gastric mucosa, intestinal metaplasia and gastric carcinoma by immunohistochemistry

Background: Carcinomas of the stomach are a heterogeneous group of lesions in terms of architecture, pattern of growth, cell differentiation, and histogenesis. Altered MUC5AC expression patterns have been reported previously in intestinal metaplasia as well as in gastric cancer. The aim of the study was to analyse the expression pattern of MUC5AC in normal, pre-neoplastic and neoplastic gastric epithelium.Methods: Formalin fixed paraffin embedded sections of sixty cases which include twenty cases of each normal gastric mucosa, intestinal metaplasia and gastric carcinoma were taken up for the study and subjected to immunohistochemistry using MUC5AC.Results: The intensity of MUC5AC immunostaining in normal gastric mucosa, intestinal metaplasia and gastric carcinoma was evaluated. Immunoreactivity was graded as 0 (negative), ± (trace positive), + (positive) or ++ (strongly positive). Statistical analysis was performed with Chi-Square test and significant differences were noted between these 3 groups (p value <0.05).Conclusions: Authors concluded that MUC5AC expression rates might be good parameters in progression of intestinal metaplasia to gastric carcinoma and might be a good prognostic marker for gastric carcinoma as it is very well implicated in understanding of gastric carcinogenesis.