Introduction

Patient-derived organoids (PDOs) are a promising preclinical cancer model that has demonstrated an advantage in predicting drug susceptibility. Norcantharidin (NCTD) derived from traditional Chinese medicine has been used in the treatment of gastric cancer, but the sensitivity of different patients to NCTD has not been evaluated in human samples.

Aims & Methods

The purpose of this study was to use PDOs to predict the drug sensitivity of NCTD in gastric cancer, so as to guide clinical drug use. PDOs were established by surgical resection of gastric cancer patients. Hematoxylin-eosin staining and immunohistochemical staining were used to identify the pathological morphology and molecular characteristics of PDOs and original tumor tissues. Genome analysis of tumor tissue and PDOs was performed using whole exon sequencing. NCTD intervention PDOs were screened for sensitivity and area under the curve (AUC) and IC50 values were assessed.

Results

10 PDOs conforming to the standard of drug sensitivity test were successfully constructed. The organoids were spherical and hollow with upper skin sac structure. The pathological and genomic features of the corresponding tumor were preserved, and the expression of related molecular markers was consistent with that of the original tissue. All PDOs could be stably passed through, frozen and resuscitated. After adding different doses of NCTD, 10 organoids showed different drug sensitivities to NCTD, among which PDO4, PDO7 and PDO10 were most sensitive to NCTD.

Conclusion

NCTD has significant anti-gastric cancer effect, but there is obvious heterogeneity in drug response. PDOs can be used as a preclinical drug screening platform to guide the development of individualized cancer treatment, and bring new hope for the research of TCM treatment of gastric cancer.

Introduction

Gastric cancer is one of the most common malignant tumors with high morbidity and mortality. Manifestations of early gastric cancer often lack specificity, leading to delayed diagnosis, with a majority of cases progressing to advanced stages upon identification. Additionally, traditional tumor markers such as CEA, CA19-9, and CA72-4 exhibit limited sensitivity and specificity. Hence, there exists an urgent imperative to discover novel predictive and diagnostic markers for early-stage gastric cancer. Unlike gastric mucosal tissue biopsy, which is restricted to localized sampling, gastric juice offers a more comprehensive and representative reflection of the overall gastric environment. However, the acidic nature of gastric juice and the presence of multiple digestive enzymes present challenges for the direct detection of protein markers in gastric juice. Exosomes, characterized by lipid bilayer membranes, serve to stabilize proteins and facilitate their transportation within the microenvironment and distant regions, thereby exerting regulatory functions and offering potential diagnostic significance.

Aims & Methods

In this study, we endeavored to identify protein markers within gastric juice exosomes of early gastric cancer patients with enhanced sensitivity and specificity. Briefly, gastric juice samples were collected from early gastric cancer patients and chronic gastritis patients matched for age and gender, who underwent gastroscopy at Peking University Third Hospital. Exosomes were isolated through ultracentrifugation. Following protein quality control, label-free quantitative proteomics was employed to investigate the differential protein composition between the two groups. Additionally, we conducted further analysis to explore the interaction among the differential proteins in the two groups with KEGG enrichment analysis. Moreover, immunohistochemical (IHC) staining, western blot and electron microscopy immunocolloid gold staining were conducted to validate the proteomic findings.

Results

The results of differential protein expression analysis indicated the presence of 21 up-regulated proteins and 32 down-regulated proteins in gastric juice exosomes of the early gastric cancer group compared to the gastritis group (fold change >2, P < 0.05). Further KEGG pathway enrichment analysis revealed that the differentially expressed proteins were primarily enriched in pathways related to glucose and lipid metabolism, immunomodulation, and the PPAR signaling pathway. In comparison to the gastritis group, the levels of CD13 protein in gastric juice exosomes were significantly increased by 7.45-fold (P = 0.043) in early gastric cancer patients. IHC staining was conducted and the results demonstrated significantly higher expression levels of CD13 in gastric mucosa tissues of gastric cancer patients compared to those of patients with gastritis, consistent with those in gastric juice exosomes. Additionally, Western blot confirmed elevated levels of CD13 in gastric juice exosomes of the early gastric cancer group compared to the gastritis group, further corroborating the proteomics findings. Furthermore, electron microscopy immunocolloid gold staining revealed predominant expression of CD13 on the membrane of gastric juice exosomes, providing a crucial basis for its subsequent direct detection through antigen-antibody recognition.

Conclusion

In summary, our findings suggested that CD13 in gastric juice exosomes may serve as a promising marker for early gastric cancer screening, aiming to facilitate early diagnosis and treatment interventions.

Introduction

Gastric Cancer has been a heavy burden in far East Asian countries. Although there are national programs in South Korea and Japan, their evidence has been suggested as insufficient. We aimed to synthesize currently available comparative data on gastric cancer mortality in healthy, asymptomatic adults by explicitly classifying the screening effects through study designs and types of intervention effects.

Aims & Methods

We searched multiple databases through October 31, 2022, for this systematic review　and meta-analysis. Studies of any design that compared gastric cancer mortality among radiographic or endoscopic screening and no screening in a community-dwelling adult population was included. The method included a duplicate assessment of eligibility, double extraction of summary data, and validity assessment using the Risk Of Bias In Non-randomized Studies of Interventions tool. Bayesian three-level hierarchical random-effects meta-analysis synthesized data corrected for self-selection bias on the relative risk (RR) for per-protocol (PP) and intention-to-screening (ITS) effects. The study registration number at PROSPERO is CRD42021277126.

Results

We included seven studies in which a screening program was newly introduced (median attendance rate, 31%; at a moderate-to-critical risk of bias) and seven cohort and eight case-control studies with ongoing screening programs (median attendance rate, 21%; all at critical risk of bias); thus, data of 1,667,117 subjects were included. For the PP effect, the average risk reduction was significant for endoscopy (RR 0.58; 95% credible interval: 0.39–0.90) but non-significant for radiography (RR 0.80; 95%CI 0.60–1.06). The ITS effect was not significant for both radiography (0.98; 95%CI 0.86–1.21) and endoscopy (RR 0.94; 95%CI 0.74–1.44). The effects' magnitude depended on the self-selection bias correction assumptions. Restricting the scope of East Asian studies only did not change the results.

Conclusion

In limited-quality observational evidence from high-prevalence regions, screening reduced gastric cancer mortality; however, the effects diminished at a program level.

Disclosure

I have no conflict of interest.

Introduction

CKLF-like MARVEL transmembrane domain containing 4 (CMTM4) plays an important role in regulation of the immune function and is involved in tumor formation and progression, but its role in gastric mucosa-related diseases remains unclear.

Aims & Methods

The aim of this study is to explore the role and mechanism of CMTM4 in gastric cancer cells.
Immunohistochemistry (IHC) was used to analyze the expression of CMTM4 in gastric biopsy. The CCK8 cell proliferation assay and plate clone formation were applied to analyze the proliferation of gastric cells. The cell scratch and transwell assay was used to analyze the migration and invasion of gastric cells, respectively. TMT proteome analysis was used to explore the possible mechanism of CMTM4 in gastric cancer cells, and verified by western blot.

Results

CMTM4 expression levels in gastric mucosal biopsy specimens from patients with gastritis and gastric cancer were analyzed by immunohistochemistry, and the results showed that CMTM4 expression was lower in gastric cancer than that in gastritis tissues (P<0.05). To investigate the function of CMTM4 in gastric cancer cell lines, we constructed CMTM4 knockdown and overexpression cells from AGS cell line and CMTM4 overexpression cells from SGC7901 cell line. The CCK8 cell proliferation assay and plate clone formation assay showed that CMTM4 overexpression significantly inhibited the proliferation of gastric cancer cells while knockdown CMTM4 promoted the proliferation of gastric cancer cells. The results of cell scratch assay showed that overexpression of CMTM4 inhibited the migration of gastric cancer cells, and knockout CMTM4 promoted the migration of gastric cancer cells. Transwell assay showed that overexpression of CMTM4 inhibited migration of gastric cancer cells and knockdown of CMTM4 promoted migration of gastric cancer cells, while knockdown of CMTM4 inhibited invasion of gastric cancer cells. In addition, overexpression of CMTM4 increased the apoptosis of gastric cancer cells. The results of TMT proteome showed that STAT1 was significantly up-regulated in gastric cancer cells overexpressing CMTM4, which was also verified by western blot.

Conclusion

CMTM4 has an oncogenic effect in gastric cancer cells. CMTM4 may affect the growth, migration and invasion of gastric cancer cells mainly through STAT1 signaling pathways.

Introduction

During gastric cancer (GC) progression, two types of metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM), are considered key pre-tumour events crucial for malignant transformation to GC. Currently, no effective therapeutic strategies target these events.

Aims & Methods

This study was performed to investigate the inhibitory efficacy and mechanism of action of luteolin (Lut) on SPEM and IM. An in vivo SPEM model was established by intraperitoneal injection of high-dose tamoxifen (TAX) in mice, and the IM models were established by treating GES-1 cells and rats with chenodeoxycholic acid (CDCA). To reveal the mechanism of action of Lut, we performed transcriptomic analysis of Lut-treated gastric corpus specimens, and quantitative chemoproteomic profiling to identify key targets of Lut.

Results

Lut-treated mice exhibited remarkable resistance to oxyntic atrophy and emergence of SPEM. Significant numbers of Lut-treated rats entered remission from IM. Transcriptomic analysis revealed that upregulated LCN2 expression in the injured mucosal region in SPEM model mice could be downregulated by Lut. LCN2 knockdown also inhibited high-dose TAX-induced SPEM formation. Quantitative chemoproteomic profiling results suggest that STAT3 is a key target of Lut and that STAT3 inhibition partially abolishes the beneficial effect of Lut.

Conclusion

Lut is a novel therapeutic candidate for SPEM and IM that can target STAT3 by downregulating LCN2 expression. These findings reveal a novel strategy for inhibiting gastric precancerous conditions.

Disclosure

The authors declare no competing interests.

Introduction

The risk of gastric cancer is expected to decrease with reduced Helicobacter pylori (H. pylori) infection rate. Although periodic endoscopic screening for gastric cancer is widely performed in East Asia, the optimal screening strategy remains unclear. Cost-effectiveness analysis (CEA) is an effective method to objectively compare different screening methods. However, no studies have compared the cost-effectiveness of endoscopy-based screening strategies.

Aims & Methods

This study aimed to determine the most cost-effective endoscopic screening strategy for the detection and treatment of gastric cancer in a modern Japanese cohort. This study consisted of two phases: clinical data collection and analysis, followed by simulation model development. The following data was retrospectively extracted from participants who received screening endoscopy between April 2019 and March 2023: age, H. pylori infection status, presence of intestinal metaplasia, pathological diagnosis of gastric cancer, and the interval between the most recent endoscopies. A Markov state transition model was constructed based on the cohort data. In this model, the prevalence of H. pylori infection and intestinal metaplasia, the transition probabilities between each state, and the probabilities of incidence of gastric cancer and treatment were defined. In the base-case analysis, the cost-effectiveness of 15 strategies with different starting ages (40/50/60 years) and screening intervals (1/2/3/4/5 years) was compared. The net monetary benefit (NMB) and incremental cost-effectiveness ratio (ICER) of quality-adjusted life-years (QALY) gained by treatment were used as outcomes. The NMB is a measure of the difference between the cost required for a strategy and the cost threshold for the same effect; the larger the NMB of a strategy, the more cost-effective it is. In contrast, a lower ICER is considered more cost-effective.

Results

A simulation model was constructed based on the cohort data of 94,137 participants (mean age 54.5 years, males 57.9%; 74.4% H. pylori-naïve, 94.2% intestinal metaplasia-negative). The results of the base-case analysis showed that the screening strategy of 4-year intervals starting at the age of 40 years had the highest net monetary benefit (97,401,578 yen) (Table). Based on the Monte Carlo simulation, the cost-effectiveness acceptability curve demonstrated that the 4-year interval screening strategy starting at the age of 40 years was superior to the other strategies when the willingness-to-pay was set at 5,000,000 yen. In one-way sensitivity analysis with a varying probability of H. pylori infection status transition, the incremental cost-effectiveness ratio was superior in the screening strategy every 4 years, starting at age 40 years.

Conclusion

Gastric cancer screening strategies can be modified in terms of cost-effectiveness in a modern Japanese cohort. Our simulation showed that endoscopic screening at 4-year intervals starting at 40 years was the most cost-effective method.

Disclosure

The authors declare that there is no conflict of interest.

Introduction

Gastric cancer screening is not formally recommended in Portugal, despite having an incidence rate of 26/100,000 inhabitants, which contrasts with recommendations from other countries with moderate incidence.

Aims & Methods

Aims: To assess the frequency of screening indications and correspondent diagnoses in patients referred for upper endoscopy from primary healthcare.
Methods: A multicenter cross-sectional study including patients who underwent upper endoscopy at 13 national endoscopy units from January to March 2024.

Results

6320 patients were included (57% male, mean age 58). Cancer screening was the indication for upper endoscopy in 1775 patients (28% of total; 52% male, mean age 60). Biopsies of the antrum and corpus were performed in 91% of those exams, and virtual chromoendoscopy was used in 19% of screening endoscopies (vs 34% for atrophic gastritis surveillance, p<0.05). Endoscopic staging for intestinal metaplasia was performed in 13%. By regions, screening indication was more common in Minho (35%) and less in the Lisbon region (15%, p<0.05 vs other regions). Only 21% of exams were considered normal, with the main findings being: erythematous gastritis (31%); atrophic gastritis (16%, 1% autoimmune gastritis), reflux esophagitis (15%), papular gastritis (10%), erosive gastritis (8%), gastric polyps (5%), erosive duodenitis (3%), peptic ulcers (3%), subepithelial lesions (1.5%) and Barrett's esophagus (0.5%). Histologically, 30% of patients had intestinal metaplasia, 5% in both the antrum and corpus. Fourteen neoplastic lesions (0.8%) were identified: 5 gastric neoplasms (0.3%), 4 superficial gastric lesions (0.2%), 2 esophagus/junction neoplasms (0.1%), 2 superficial junction lesions (0.2%), and 1 ampulloma (0.1%). Ten percent of patients would require future endoscopic surveillance.

Conclusion

A significant proportion of upper endoscopies in Portugal are already performed for cancer screening, which seems justifiable given the high proportion of clinically relevant alterations identified. The low proportion of exams with chromoendoscopy suggests that measures are needed to increase the use of this technique in clinical practice.