The majority of patients with advanced esophageal or gastric cancer do not start palliative systemic treatment. To gain insight into the considerations underlying the decision not to start systemic treatment, we analyzed characteristics of patients starting and not starting systemic treatment, reasons for not starting systemic treatment, and receipt of local palliative treatments on a nationwide scale. Patients diagnosed with advanced esophageal or gastric cancer between 2015 and 2021 were included (n = 10,948). Survival was compared using propensity score matching on patient and disease characteristics. Most patients did not start systemic treatment (esophageal cancer 59%; gastric cancer 64%). These patients were generally older, more often female, had more comorbidities and a worse performance status. The main reason for not starting systemic treatment was patient or family preference (35%). Among patients who did not start systemic treatment, 47% (esophageal) and 19% (gastric), received local palliative treatment, most commonly radiotherapy. Patients who did not start systemic treatment had worse median overall survival compared to patients who did start (esophageal cancer 2.9 months vs. 8.9 months; gastric cancer 2.2 vs. 8.2 months). These findings indicate that patient condition and disease burden are important aspects in systemic treatment decisions. However, patient or family preference was the main reason for not starting systemic treatment, highlighting that their priorities also strongly influence the decision. Systemic treatment did show to be associated with improved overall survival in matched patients, and therefore adequately weighing treatment risks and benefits based on real world data against patient preferences is of utmost importance.

Within the tumor microenvironment (TME), the association of B lymphocytes (B cells) with prognosis and therapy response in gastric cancer (GC) remains poorly characterized. We investigated the predictive and prognostic value of B cells, including their spatial organization within the TME, in one of the largest multi-cohort studies to date.

Using CD20 immunohistochemistry, we evaluated B cell density in resection specimens from 977 patients with resectable GC across three cohorts, including the randomized phase III Korean CLASSIC trial. The relationship between CD20 density, clinicopathological characteristics, and overall survival (OS) was analyzed. Digital spatial profiling of 1063 regions of interest from 15 patients was performed to characterize B cell distribution within different regions of interest (ROIs) using the NanoString GeoMx platform.

CD20 density was significantly higher in diffuse-type GC compared to intestinal-type (p = 0.000012). Patients with CD20-low diffuse-type GC had the shortest OS in the CLASSIC trial (median OS: 49 vs 62 months, HR: 1.9, 95% CI: 1.2-3.0, p = 0.003) and in a Japanese cohort (median OS: 49 vs 67 months, HR: 2.2, 95% CI: 1.2-4.0, p = 0.011). This survival difference was not seen in patients treated with adjuvant chemotherapy (median OS: 62 vs 63 months, HR: 1.8, 95% CI: 0.88-3.5, p = 0.108). Spatial profiling revealed significant B cell enrichment within tumor ROIs compared to the stroma, particularly in diffuse-type GC.

Low CD20 positivity, especially in diffuse-type GC, is linked to poor prognosis and may identify patients who could benefit from chemotherapy. These findings underscore the role of B cells in GC.

At a population level, the European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter and Microbiota Study Group (EHMSG), and the European Society of Pathology (ESP) suggest endoscopic screening for gastric cancer (and precancerous conditions) in high-risk regions (age-standardized rate [ASR] > 20 per 100 000 person-years) every 2 to 3 years or, if cost-effectiveness has been proven, in intermediate risk regions (ASR 10-20 per 100 000 person-years) every 5 years, but not in low-risk regions (ASR < 10).ESGE/EHMSG/ESP recommend that irrespective of country of origin, individual gastric risk assessment and stratification of precancerous conditions is recommended for first-time gastroscopy. ESGE/EHMSG/ESP suggest that gastric cancer screening or surveillance in asymptomatic individuals over 80 should be discontinued or not started, and that patients' comorbidities should be considered when treatment of superficial lesions is planned.ESGE/EHMSG/ESP recommend that a high quality endoscopy including the use of virtual chromoendoscopy (VCE), after proper training, is performed for screening, diagnosis, and staging of precancerous conditions (atrophy and intestinal metaplasia) and lesions (dysplasia or cancer), as well as after endoscopic therapy. VCE should be used to guide the sampling site for biopsies in the case of suspected neoplastic lesions as well as to guide biopsies for diagnosis and staging of gastric precancerous conditions, with random biopsies to be taken in the absence of endoscopically suspected changes. When there is a suspected early gastric neoplastic lesion, it should be properly described (location, size, Paris classification, vascular and mucosal pattern), photodocumented, and two targeted biopsies taken.ESGE/EHMSG/ESP do not recommend routine performance of endoscopic ultrasonography (EUS), computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)-CT prior to endoscopic resection unless there are signs of deep submucosal invasion or if the lesion is not considered suitable for endoscopic resection.ESGE/EHMSG/ESP recommend endoscopic submucosal dissection (ESD) for differentiated gastric lesions clinically staged as dysplastic (low grade and high grade) or as intramucosal carcinoma (of any size if not ulcerated or ≤ 30 mm if ulcerated), with EMR being an alternative for Paris 0-IIa lesions of size ≤ 10 mm with low likelihood of malignancy.ESGE/EHMSG/ESP suggest that a decision about ESD can be considered for malignant lesions clinically staged as having minimal submucosal invasion if differentiated and ≤ 30 mm; or for malignant lesions clinically staged as intramucosal, undifferentiated and ≤ 20 mm; and in both cases with no ulcerative findings.ESGE/EHMSG/ESP recommends patient management based on the following histological risk after endoscopic resection: Curative/very low-risk resection (lymph node metastasis [LNM] risk < 0.5 %-1 %): en bloc R0 resection; dysplastic/pT1a, differentiated lesion, no lymphovascular invasion, independent of size if no ulceration and ≤ 30 mm if ulcerated. No further staging procedure or treatment is recommended.Curative/low-risk resection (LNM risk < 3 %): en bloc R0 resection; lesion with no lymphovascular invasion and: a) pT1b, invasion ≤ 500 µm, differentiated, size ≤ 30 mm; or b) pT1a, undifferentiated, size ≤ 20 mm and no ulceration. Staging should be completed, and further treatment is generally not necessary, but a multidisciplinary discussion is required. Local-risk resection (very low risk of LNM but increased risk of local persistence/recurrence): Piecemeal resection or tumor-positive horizontal margin of a lesion otherwise meeting curative/very low-risk criteria (or meeting low-risk criteria provided that there is no submucosal invasive tumor at the resection margin in the case of piecemeal resection or tumor-positive horizontal margin for pT1b lesions [invasion ≤ 500 µm; well-differentiated; size ≤ 30 mm, and VM0]). Endoscopic surveillance/re-treatment is recommended rather than other additional treatment. High-risk resection (noncurative): Any lesion with any of the following: (a) a positive vertical margin (if carcinoma) or lymphovascular invasion or deep submucosal invasion (> 500 µm from the muscularis mucosae); (b) poorly differentiated lesions if ulceration or size > 20 mm; (c) pT1b differentiated lesions with submucosal invasion ≤ 500 µm with size > 30 mm; or (d) intramucosal ulcerative lesion with size > 30 mm. Complete staging and strong consideration for additional treatments (surgery) in multidisciplinary discussion.ESGE/EHMSG/ESP suggest the use of validated endoscopic classifications of atrophy (e. g. Kimura-Takemoto) or intestinal metaplasia (e. g. endoscopic grading of gastric intestinal metaplasia [EGGIM]) to endoscopically stage precancerous conditions and stratify the risk for gastric cancer.ESGE/EHMSG/ESP recommend that biopsies should be taken from at least two topographic sites (2 biopsies from the antrum/incisura and 2 from the corpus, guided by VCE) in two separate, clearly labeled vials. Additional biopsy from the incisura is optional.ESGE/EHMSG/ESP recommend that patients with extensive endoscopic changes (Kimura C3 + or EGGIM 5 +) or advanced histological stages of atrophic gastritis (severe atrophic changes or intestinal metaplasia, or changes in both antrum and corpus, operative link on gastritis assessment/operative link on gastric intestinal metaplasia [OLGA/OLGIM] III/IV) should be followed up with high quality endoscopy every 3 years, irrespective of the individual's country of origin.ESGE/EHMSG/ESP recommend that no surveillance is proposed for patients with mild to moderate atrophy or intestinal metaplasia restricted to the antrum, in the absence of endoscopic signs of extensive lesions or other risk factors (family history, incomplete intestinal metaplasia, persistent H. pylori infection). This group constitutes most individuals found in clinical practice.ESGE/EHMSG/ESP recommend H. pylori eradication for patients with precancerous conditions and after endoscopic or surgical therapy.ESGE/EHMSG/ESP recommend that patients should be advised to stop smoking and low-dose daily aspirin use may be considered for the prevention of gastric cancer in selected individuals with high risk for cardiovascular events.

To develop a nomogram based on clinical features and spectral quantitative parameters to preoperatively predict the Lauren classification for locally advanced gastric cancer (LAGC).

Patients diagnosed with LAGC by postoperative pathology who underwent abdominal triple-phase enhanced spectral computed tomography (CT) were prospectively enrolled in this study between June 2023 and December 2023. All the patients were categorized into intestinal- and diffuse-type groups according to the Lauren classification. Traditional characteristics, including demographic information, serum tumor markers, gastroscopic pathology, and image semantic features, were collected. Spectral quantitative parameters, including iodine concentration (IC), effective atomic number (Zeff), and slope of the energy spectrum curve from 40 keV to 70 keV (λ), were measured three times for each patient by two blinded radiologists in arterial/venous/delayed phases (AP/VP/DP). Differences in traditional features and spectral quantitative parameters between the two groups were compared using univariable analysis. Independent predictors of the Lauren classification of LAGC were screened using multivariable logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was used to assess the discriminating capability. Ultimately, the nomogram, including clinical features and spectral CT quantitative parameters, was developed.

Gender, nIC in AP (APnIC), and λ in DP (λd) were independent predictors for Lauren classification. The nomogram based on these indicators produced the best performance with an area under the curve of 0.841 (95% confidence interval: 0.749-0.932), specificity of 85.3%, accuracy of 76.4%, and sensitivity of 68.4%.

The nomogram based on clinical features and spectral CT quantitative parameters exhibits great potential in the preoperative and non-invasive assessment of Lauren classification for LAGC.

Question Can the proposed nomogram, integrating clinical features and spectral quantitative parameters, preoperatively predict the Lauren classification in locally advanced gastric cancer (LAGC)? Findings The nomogram, based on gender, arterial phase normalized iodine concentration, and slope of the energy spectrum curve in the delayed phase showed satisfactory predictive ability. Clinical relevance The established nomogram could contribute to guiding individualized treatment strategies and risk stratification in patients by predicting the Lauren classification for LAGC before surgery.

Alpha-fetoprotein-producing gastric carcinoma (AFPGC) is an aggressive subtype of gastric cancer characterized by a primitive cellular phenotype and poor prognosis. The tumor immunology of AFPGC remains largely unexplored. Given its embryonic-like properties, AFPGC is hypothesized to employ distinct immune evasion strategies, with the oncofetal protein human leukocyte antigen (HLA)-G-a key mediator of maternal-fetal immune tolerance-likely playing a pivotal role. To test this, we assessed the expression of HLA-G, along with other key immune evasion markers, including HLA class I (HLA-I) deficiency and PD-L1 expression, in 39 cases of AFPGC, and compared them with those of 44 Epstein-Barr virus (EBV)-positive, 57 microsatellite instability (MSI), 54 intestinal-type, and 45 diffuse-type gastric carcinomas. HLA-G expression was significantly higher in AFPGCs (71%) than in other subtypes (7-28%; P < 0.001). HLA-I deficiency (≥ 1% of tumor cells) was most prevalent in AFPGC (69%), followed by MSI tumors (56%), with lower rates in other subtypes (22-29%). PD-L1 positivity (combined positive score ≥ 5) was observed in 41% of AFPGCs, lower than in EBV-positive (77%) and MSI tumors (44%), but higher than in intestinal-type (13%) and diffuse-type (9%) carcinomas. Furthermore, CD8-positive T-cell infiltration was found to be lowest in AFPGC compared to the other subtypes. These findings suggest that AFPGC employs multiple immune evasion mechanisms, notably through increased HLA-G expression and HLA-I deficiency, likely linked to its primitive cellular phenotype and reactivation of immunogenic oncofetal antigens. Such immune evasion features may underlie the aggressiveness of AFPGC and present promising targets for immunotherapeutic interventions.

Mitochondria have their own genome (mtDNA), which in humans is a circular multi-copy genome consisting of 16 569 base pairs. Abnormalities in the mtDNA have been reported to correlate with various age-related pathophysiologies.

Based on a total of 182 DNA samples extracted from gastric cancer tissues, we measured mtDNA copy numbers (mtDNA-CN) using real-time polymerase chain reaction (PCR) and then examined alongside sex, age, tumor stage, Laurén classification, and the overexpression of Human Epidermal Growth Factor Receptor 2 (HER2).

We found no sex differences in mtDNA-CN and no correlation with age, but significant differences according to tumor stage. The mtDNAcn of intestinal type by Laurén classification was significantly larger than that of diffuse type. There was no significant difference in mtDNA-CN between HER2-positive and -negative tissues. Multiple regression analyses showed that only the tumor stage was a significant variable, while Laurén classification was not.

These results indicate that mitochondrial genomic abnormalities contribute the progression of gastric cancer independently of HER2 overexpression, and may shed light on the emerging role of mtDNA-CN in situ as a possible biomarker for estimating cancer progression.

Poorly differentiated gastric cancer (PDGC) is characterized by high invasiveness, rapid progression, and poor prognosis for patients. Differentiation therapy has long been a promising approach by manipulating the differentiation state of tumor cells to inhibit tumor growth, offering fewer side effects. Decitabine (DAC), is known as an inhibitor of DNA methylation, thus reactivating the transcription of previously methylated silenced genes associated with differentiation to induce a more differentiated state. This study used the differentiation-inducing agents DAC to treat two PDGC cell lines, MKN45 and NUGC4, and explored the impact of DAC on cell proliferation and influence of their sensitivity to Natural Killer cells (NK cells) mediated cytotoxicity. The results demonstrated a significant reduction in cell proliferation, migration, and invasion without affecting cell viability after DAC treatment. Additionally, transcriptomic analysis revealed that DAC-treated PDGC cells upregulated multiple immune-related genes, including the gene encoding for tumor necrosis factor alpha (TNF-α). Co-culture study of NK cells and PDGC cells showed that DAC treatment enhanced the sensitivity of these cancer cells to NK cell-mediated cytotoxicity, and TNF-α played a crucial role in promoting NK cell cytotoxicity. Following the subcutaneous implantation of tumors in nude mice, DAC administration significantly inhibited the growth of PDGC tumors and induced the upregulation of differentiation related genes. In summary, DAC effectively reduces the malignant characteristics of the PDGC cells by promoting their transition towards a higher state of differentiation and enhancing their sensitivity to NK cell-mediated killing, providing new insights for the mechanisms of the antitumor effects of DAC.

Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids.

Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model.

AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG.

Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.

This study aimed to define an optimal age cutoff for early-onset gastric cancer (EOGC) and compare its characteristics with those of late-onset gastric cancer (LOGC) using nationwide survey data.

Using data from a nationwide survey, this comprehensive population-based study analyzed data spanning 3 years (2009, 2014, and 2019). The joinpoint analysis and interrupted time series (ITS) methodology were employed to identify age cutoffs for EOGC based on the sex ratio and tumor histology. Clinicopathologic characteristics and surgical outcomes were compared between the EOGC and LOGC groups.

The age cutoff for defining EOGC was suggested to be 50 years, supported by joinpoint and ITS analyses. Early gastric cancer was predominantly present in the EOGC and LOGC groups. Patients with EOGC comprised 20.3% of the total study cohort and demonstrated a more advanced disease stage compared to patients with LOGC. However, patients with EOGC underwent more minimally invasive surgeries, experienced shorter hospital stays, and had lower postoperative morbidity and mortality rates.

This study proposes an age of ≤50 years as a criterion for defining EOGC and highlights its features compared to LOGC. Further research using this criterion should guide tailored treatment strategies and improve outcomes for young patients with gastric cancer.

KMT2C and KMT2D ( KMT2C/D ) are frequently mutated in gastric adenocarcinoma, yet their function in cancer initiation remains poorly understood. In this study, based on the observation that loss-of-function mutations of KMT2C and KMT2D are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models to selectively knock out Kmt2c and Kmt2d in gastric epithelial cells with Tmprss2-CreER T2 . Through histological staining and single-cell RNA sequencing, we observed that Kmt2c/d loss led to nuclear dysplasia and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks post Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human gastric adenocarcinoma. Kmt2c/d knockout reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering sensitivity to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTROC1 inhibition and anti-PD1 immunotherapy significantly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c / d loss in gastric cancer initiation and suggest the potential therapeutic strategies for KMT2C/D -deficient gastric cancer.

The mechanism of tumor budding (TB) in gastric adenocarcinoma (GAC) and its relationship with biological indicators and prognostic significance, remains unclear. In this study, we conducted a comprehensive analysis using whole-slide imaging to evaluate TB in 75 cases of GAC. Our findings revealed the risk factors associated with TB in GAC and their impact on patient prognosis. The results indicate that the majority of cases exhibited a TB grade exceeding 10 (n=41), followed by 6-10 (n=15). Histologic grade (R=0.26, P =0.06), pT stage (R=0.56, P =0.00), neural invasion (R=0.29, P =0.01), marginal zone growth pattern (R=0.25, P =0.02), and basal zone growth pattern (R=0.38, P =0.001) are associated with TB in GAC. Logistic regression analysis revealed that the infiltrative growth pattern in both the marginal zone (odds ratio=5.90, 95% CI: 1.04-33.44, P =0.05) and basal zone (odds ratio=12.80, 95% CI: 2.03-80.68, P =0.01) were identified as risk factors for TB in GAC. Univariate analysis demonstrated a negative correlation between TB and TB grade with overall survival and progression-free survival in GAC patients. Furthermore, the multivariate COX analysis revealed that TB and TB grade, along with American Joint Committee on Cancer stage, lymph node metastasis, and pT stage, independently influenced the prognosis of GAC patients. In conclusion, a comprehensive evaluation of TB could serve as a significant histologic marker for risk stratification in GAC.

Specific types of gastric tumors, including gastric linitis plastica and lymphoma, may cause extensive deep-layer infiltration, impeding an accurate diagnosis with endoscopic biopsy. This study aims to evaluate the efficacy of endoscopic ultrasound (EUS)-guided bite-on-bite biopsy and EUS-guided fine-needle aspiration (EUS-FNA) in diagnosing gastric malignancies with negative endoscopic biopsies.

We retrospectively analyzed suspicious malignant gastric lesion cases in our hospital from October 2017 to August 2023. Clinical manifestations, radiographical examinations, endoscopic examinations, histopathological results, and therapeutic strategies were recorded and analyzed.

Forty malignant gastric tumor cases with negative endoscopic biopsies were incorporated into our study. EUS-guided bite-on-bite biopsy was performed in 16 cases exclusively, whereas 17 patients received EUS-FNA exclusively, and seven patients underwent both simultaneously. Among the 23 patients who received the EUS-guided bite-on-bite biopsy, 22 (95.7%) were diagnosed with malignancies. Among the 24 patients who received EUS-FNA, a total of 19 cases with malignancies (79.2%) were confirmed by EUS-FNA (p = 0.11): 13 gastric adenocarcinomas, five metastatic malignancies, and one malignant stromal tumor. No adverse events were observed in any of the cases.

EUS-guided bite-on-bite biopsy and EUS-FNA possess their advantages and disadvantages. EUS-guided bite-on-bite biopsy could serve as a reliable diagnostic method for shallow lesions with negative malignant endoscopic biopsies.

Gastric cancer remains a leading cause of cancer-related mortality worldwide. In the United States, gastric cancer incidence and mortality are substantially higher among non-White racial and ethnic groups and new immigrants from high-incidence countries. This is in large part related to the higher prevalence of Helicobacter pylori -associated gastric premalignant changes in these populations. Apart from primary prevention, early detection of gastric cancer is the principal strategy to reduce gastric cancer mortality and improve survival. Extensive evidence in Asian countries has demonstrated the benefits of endoscopic screening in detecting early-stage gastric cancer and reducing gastric cancer-related mortality. By contrast, direct, high-quality US-based data, such as from large clinical trials or observational studies, on important outcomes of gastric cancer screening are still lacking. In this review, we evaluate and summarize the latest global evidence on the epidemiology and predisposing factors of gastric cancer as well as the efficacy, benefits vs. risks, and cost-effectiveness of gastric cancer screening. We further discuss the critical knowledge gaps and challenges in promoting gastric cancer screening in the United States. Dedicated research is urgently needed to enrich the US-based data on gastric cancer primary and secondary prevention to inform clinical practice and reduce gastric cancer-related morbidity and mortality in a cost and resource efficient manner.

Gastric cancer is an inflammation-driven disease often associated with a bad prognosis. Upstream stimulatory factors USF1 and USF2 are pleiotropic transcription factors, with tumor suppressor function. Low expression of USF1 is associated with low survival in gastric cancer patients. USF1 genetic polymorphism -202G > A has been associated with cancer susceptibility. Our aim was to investigate USF1 gene polymorphism and serum level with the risk of gastric cancer.

USF1-202 G/A polymorphism was analyzed by sanger sequencing, with the measure of USF1/USF2 serum levels by ELISA in H. pylori-positive patients with chronic gastritis, gastric precancerous lesions, gastric cancer and in healthy controls.

Our results show that the presence of the USF1-202 A allele increased the risk of gastric cancer compared to G (OR = 2; 95% CI 1.07-3.9; P = 0.02). Genotypically and under the dominant mutation model, the combined USF1- GA/AA -202 genotypes corresponded to higher risk of gastric cancer (OR = 3.5; 95% CI 1.4-8.2; p-value = 0.005) than the GG genotype. Moreover, the G/A transition at USF1-202 was associated with lower USF1 serum level, and mostly observed in gastric cancer patients where the average serological level of USF1 were 2.3 and twofold lower for the AA and GA genotypes, respectively, compared to GG.

USF1-202 G/A polymorphism constitutes a gastric cancer genetic risk factor. Together with USF1/USF2 serum level, they can be proposed as promising biomarkers for gastric cancer detection/prevention.

Gastric adenocarcinoma (GAC) imposes a considerable global health burden. Molecular profiling of GAC from the tumor microenvironment perspective through a multi-omics approach is eagerly awaited in order to allow a more precise application of novel therapies in the near future.

To better understand the tumor-immune interface of GAC, we identified an internal cohort of 82 patients that allowed an integrative molecular analysis including mutational profiling by whole-exome sequencing, RNA gene expression of 770 genes associated with immune response, and multiplex protein expression at spatial resolution of 34 immuno-oncology targets at different compartments (tumorous cells and immune cells). Molecular findings were validated in 595 GAC from the TCGA and ACRG external cohorts with available multiomics data. Prediction of response to immunotherapies of the discovered immunophenotypes was assessed in 1039 patients with cancer from external cohorts with available transcriptome data.

Unsupervised clustering by gene expression identified a subgroup of GAC that includes 52% of the tumors, the so-called Inflamed class, characterized by high tumor immunogenicity and cytotoxicity, particularly in the tumor center at protein level, with enrichment of PIK3CA and ARID1A mutations and increased presence of exhausted CD8+ T cells as well as co-inhibitory receptors such as PD1, CTLA4, LAG3, and TIGIT. The remaining 48% of tumors were called non-inflamed based on the observed exclusion of T cell infiltration, with an overexpression of VEGFA and higher presence of TP53 mutations, resulting in a worse clinical outcome. A 10-gene RNA signature was developed for the identification of tumors belonging to these classes, demonstrating in evaluated datasets comparable clinical utility in predicting response to current immunotherapies when tested against other published gene signatures.

Comprehensive immunophenotyping of GAC identifies an inflamed class of tumors that complements previously proposed tumor-based molecular clusters. Such findings may provide the rationale for exploring novel immunotherapeutic approaches for biomarker-enriched populations in order to improve GAC patient's survival.

Gastric cancer (GC) is the 5th most common malignancy worldwide. Adenocarcinoma accounts for 95% of all GC. While most cases of gastric adenocarcinoma (GAC) arise in older age males, a significant proportion of biological disparity exists between different ages. In this study, we aim to compare the demographics and prognostic outcomes of different ages of patients with GAC.

This retrospective study utilized the GAC cases abstracted from the Surveillance, Epidemiology, and End Results Program's 17 registries dataset from 2000 to 2020. Cases were divided into different age group brackets to comparatively explore characteristics of GAC.

A total of 103,674 cases were identified. The median age was 69 years, with a significant proportion 39.7% (n = 41,154) falling within the 66-80 age bracket cases. Female proportions were higher in the ≤ 35 years age group 47.2% (n = 960) and ≥ 81 years age group 45.7% (n = 9,695). About 45.1% (n = 916) of ≤ 35 years age group cases were Hispanic, while 60% (n = 12,715) of ≥ 81 years age group cases were non-Hispanic White. Ages between 51-65 and 66-80 years had higher proportions of liver metastasis 17% and 16% than their younger and older peers. Age ≤ 35 years cases are more likely to present at cardia 20.5%. Male gender had the worst survival across all age groups, with the worst in the ≤ 35 age group hazard ratio (H.R) 1.22(1.007 - 1.250 p < 0.001). Black had the worst survival across all ages, with the worst in the ≤ 35 years age group H.R 1.405 (1.164 - 1.696 p < 0.001). When plotted against other races in each age group, Hispanics had poor survival at young ages H.R 1.224 (1.069 - 1.401) and superior survival at older ages, with H.R 0.944 (0.902 - 0.987) in the ≥ 81 age group. Tumors located in the greater curvature and overlapping lesions demonstrated worse prognosis compared to cardia. Conversely, tumors in the pylorus and lesser curvature generally exhibited better prognosis.

In the United States GAC predominantly affects older adults, but early-onset cases exhibit aggressive histologies and poor survival, particularly more common in Hispanics. Black individuals face the worst survival outcomes across all age groups. Gender inclination towards males shrinks at the extremes of ages. At different age brackets, the demographics and prognosis changes, necessitating customized interventions.

Gastric cancer (GC) is a highly heterogeneous tumour with high morbidity. Approximately 95% of GC cases are gastric adenocarcinomas, which are further categorized into two predominant subtypes: diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC). These subtypes exhibit distinct pathophysiological and molecular characteristics, reflecting their unique tumorigenic mechanisms.

In this study, we employed a comprehensive approach to identify driver genes associated with DGC and IGC by focusing on copy number variation (CNV) genes within the competing endogenous RNA (ceRNA) network. The influence of driver CNV genes on the molecular, cellular, and clinical differences between DGC and IGC was subsequently analysed. Finally, therapeutic strategies for DGC and IGC were evaluated based on the status and functional pathways of the driver CNV genes.

A total of 17 and 22 driver CNV genes were identified in DGC and IGC, respectively. These genes drive subtype differences through the ceRNA network, resulting in alterations in the tumour microenvironment (TME). Based on these differences, personalized treatment strategies for DGC or IGC could be developed. Immune checkpoint inhibitors may be an effective treatment option in IGC. Additionally, DGC patients with homozygous deletion of PPIF might benefit from adjuvant chemotherapy, whereas those with high-level amplification of MTAP could respond to targeted therapy.

Driver CNV genes were identified to reveal the underlying cause of heterogeneity in DGC and IGC. Furthermore, specific driver CNV genes were identified as potential therapeutic targets, facilitating personalized treatment.

Helicobacter pylori ( Hp ) and gastric atrophy represent significant risk factors for gastric cancer (GC). Nevertheless, to date, no nomogram has been developed to predict GC based on the specific combination of risk factors present in individual cases.

A retrospective cohort study was conducted using health screening data collected between 2003 and 2018. Subjects with positive results for anti- Hp antibody were enrolled. Individuals were classified into 4 groups: low-B (low titer without atrophy), high-B (high titer without atrophy), high-C (high titer with atrophy), and low-C (low titer with atrophy). Nomogram prediction models were developed for overall GCs as well as intestinal and diffuse cancers, with each type considered a competing event, by using both Cox proportional and subdistribution hazard models. Prediction performance was evaluated using the concordance index (c-index) and the area under the curve through 10-fold cross-validation.

During a median follow-up period of 5.7 years, 231 new GC cases developed among the total cohort of 28,311 subjects, including 159 intestinal type, 68 diffuse type, and 4 cases of unknown type. Multivariable analyses indicated that age, body mass index, family history, smoking, and classification into the high-C or low-C group were significant predictors of GC. The nomograms for intestinal type, diffuse type, and total GC demonstrated area under the curve values of 0.82, 0.62, and 0.75, respectively, and c-indices of 0.85, 0.54, and 0.76, respectively.

The nomograms for GC prediction would be useful in identifying high-risk individuals, particularly for intestinal type. This would facilitate the implementation of personalized eradication and intensive screening strategies to target those at higher risk for GC.

Lipid rafts are highly heterogeneous and dynamic microdomains involved in molecule trafficking and signaling transduction. This study investigates the role of lipid rafts in gastric cancer and their key regulators. Analyzing FFPE samples from 111 gastric cancer patients, we found that high lipid raft levels predict poor prognosis. Modulating these levels in gastric cancer cell lines significantly impacted cell proliferation, migration, and invasion. Weighted Gene Co-expression Network Analysis identified AXL as a hub gene associated with lipid rafts. AXL knockdown experiments revealed its interaction with Caveolin-1, a caveolae lipid raft protein, which regulates lipid raft levels and promotes AKT and ERK signaling, enhancing cancer development and metastasis. In vivo tumorigenesis assays and survival analyses further supported these findings. This study underscores the significance of lipid rafts in gastric cancer and identifies AXL as a novel regulator, offering new insights into the molecular mechanisms of cancer progression and suggesting potential therapeutic targets.

Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries.

Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries. Formalin-fixed paraffin-embedded primary tumour endoscopic biopsy samples were collected and submitted for central morphological and immunohistochemical characterization and TP53 molecular assessment and Helicobacter pylori infection.

A total of 259 patients were included in the study: 137 (53%) from LATAM and 122 (47%) from Europe. Significant biological differences were detected between European and LATAM patients. Low representation of chromosomal instability (CIN) and HER2 positive cases were found in LATAM. MUC6 and PD-L1 were more frequently overexpressed in European cases, showing a significant correlation across the entire study population, with this association being especially pronounced in MMRdeficient cases. Both TP53 mutation by next-generation sequencing and p53 immunohistochemical aberrant pattern were linked with features associated with chromosomal instability. No regional differences were observed in H. pylori prevalence or abundance, indicating that the afore mentioned variations cannot be attributed to this factor.

Our findings underscore a need for region-specific approaches in gastroesophageal cancer diagnosis and treatment. MUC6 emerges as a putative immune regulator that needs further investigation. Research tailored to the unique biological profiles in different global regions is crucial to effectively address the observed disparities.

The Cancer Genome Atlas (TCGA) classifies gastric cancer (GC) into four molecular subtypes: Epstein-Barr virus-positive, microsatellite instability-high (MSI-H), genomically stable (GS), and chromosomal instability (CIN). This exploratory analysis compared the genomic landscape of late-stage GC from KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 studies with early-stage GC from TCGA and evaluated the genomic characteristics of late-stage GC in patients of Western and Asian origin.

Using pretreatment tumor samples, bulk DNA was analyzed via whole-exome sequencing (WES; KEYNOTE-059/KEYNOTE-061) and FoundationOneCDx (KEYNOTE-062) to determine TCGA-defined molecular subtypes (only MSI-H is determinable from FoundationOneCDx), genomic alterations, homologous recombination deficiency (HRD), and tumor mutational burden (TMB); gene expression signatures were analyzed using RNA sequencing.

When comparing KEYNOTE-059/061/062 combined WES and FoundationOneCDx data with data from TCGA, the MSI-H subtype prevalence was numerically lower in patients of Western (5% v 22%) and Asian origin (5% v 19%). When comparing KEYNOTE-059/061 WES data with the TCGA data set, the GS subtype prevalence was numerically higher (36% v 21%) in patients of Western or Asian origin. Among subtypes in KEYNOTE-059/061, HRD scores and TMB trended highest in CIN and MSI-H subtypes, respectively. TP53 mutation was the most prevalent genomic characteristic per KEYNOTE-059/061/062 combined analysis in patients of Western or Asian origin. Gene expression signature distributions were generally similar between patients of Western and Asian origin.

Numerical differences in the prevalence of MSI-H and GS subtypes were observed between early-stage and late-stage GC. Genomic characteristics of late-stage GC were generally similar between patients of Western and Asian origin.

Lymphatic route is the main pathway for gastric cancer (GC) spread, and lymph node (LN) involvement is a major prognostic factor after curative resection. The aim of this study was to assess the outcomes of specific LN station dissection.

Patients with locally advanced (cT2-4N0-3M0) GC who underwent multimodal treatment between 2013 and 2023 were included in the study. Patients who had not undergone gastrectomy, had early (cT1) or metastatic GC, who had undergone multiorgan resections, palliative care, had died before the end of curative-intent planned treatment, or had incomplete clinical or pathological information were excluded. The primary endpoint was the development of serious complications, and the secondary outcome was OS.

Mulivariable analysis revealed, that among patients who received neoadjuvant chemotherapy (NAC), it was observed that station 10 lymphadenectomy was associated with a higher risk of serious postoperative complications. (27.6 % vs 8.7 %; OR = 3.28) Among the no-NAC group, it was observed that station 13 lymphadenectomy was associated with a higher risk of serious postoperative complications. (57.1 % vs 13.2 %; OR = 6.96). Among the NAC group, a lower risk of death was observed in patients with station 8 (HR = 0.53) or 11 lymphadenectomy (HR = 0.53).

While D2 lymphadenectomy remains crucial, particularly in in high-volume, experienced GC centers, the necessity of a more extensive D2+ lymphadenectomy is not supported by our findings. Moreover, we aimed to highlight the importance of tailored surgical approaches and emphasize the significance of LN station dissection in influencing both short-term complications and long-term survival outcomes.

Intestinal-type gastric cancer (IGC) and diffuse-type gastric cancer (DGC) exhibit different prevalence rates between sexes. While environmental factors like Helicobacter pylori infection and alcohol consumption contribute to these differences, they do not fully account for them, suggesting a role for host genetic factors.

We conducted a meta-analysis to explore associations between single nucleotide polymorphisms (SNPs) and the risk of IGC or DGC. The analysis included the SNUBH cohort (998 participants: 159 DGCs, 303 IGCs, 4,962,361 variants) and the GC_HC cohort (6,233 participants: 389 DGCs, 405 IGCs, 4,541,617 variants). Significant variants were validated in the SNUBH2_AA cohort (5,511 participants: 40 DGCs, 49 IGCs, 3,668,632 variants).

The meta-analysis identified that rs762855 (chr4:3,074,795; hg19) is significantly associated with DGC risk in females (OR [95% CI]: 1.758 [1.438-2.150], P = 3.91 × 10-8), a finding replicated in the SNUBH2_AA datasets (OR [95% CI]: 3.356 [1.031-10.92], P = 4.43 × 10-2). Gene-set and transcriptomic analyses revealed that the Myb/SANT DNA Binding Domain Containing 1 (MSANTD1) gene is significantly linked to DGC susceptibility in females. In addition, Mendelian randomization analyses suggested that increased serum total protein and non-albumin protein (NAP) levels elevate DGC risk in females (P < 0.05), but not in males.

The rs762855 SNP, MSANTD1, and serum NAP levels are associated with DGC risk in Korean females.

Histone lactylation, a novel epigenetic modification, is regulated by the lactate produced by glycolysis. Glycolysis is activated in various cancers, including gastric cancer (GC). However, the molecular mechanism and clinical impact of histone lactylation in GC remain poorly understood. Here, we demonstrate that histone H3K18 lactylation (H3K18la) is elevated in GC, correlating with a worse prognosis. SIRT1 overexpression decreases H3K18la levels, whereas SIRT1 knockdown increases H3K18la levels in GC cells. RNA-seq analysis demonstrates that lncRNA H19 is markedly downregulated in GC cells with SIRT1 overexpression and those grown under glucose free condition, which confirmed decreased H3K18la levels at its promoter region. H19 knockdown decreased the expression levels of LDHA and H3K18la, and LDHA knockdown impaired H19 and H3K18la expression, suggesting an H19/glycolysis/H3K18la-positive feedback loop. Combined treatment with low doses of the SIRT1-specific activator SRT2104 and the LDHA inhibitor oxamate exerted significant antitumor effects on GC cells, with limited adverse effects on normal gastric cells. The SIRT1-weak/H3K18la-strong signature was found to be an independent prognostic factor in patients with GC. Therefore, SIRT1 acts as a histone delactylase for H3K18, and loss of SIRT1 triggers a positive feedback loop involving H19/glycolysis/H3K18la. Targeting this pathway serves as a novel therapeutic strategy for GC treatment.

Gastric cancer (GC) is recognized for intrinsic heterogeneity, although it is similarly approached in Europe and Latin America (LATAM). The LEGACY project aimed to deepen GC molecular understanding through multi-omics analysis in Europe and LATAM GC samples.

Tumor samples were centrally reviewed for histology, human epidermal growth factor receptor 2 (HER2) expression, and mismatch repair-deficient (dMMR)/microsatellite instability (MSI) status. In addition, we assessed Epstein-Barr virus (EBV) status, programmed death-ligand 1 (PD-L1) combined positive score (CPS), and carried out tissue genomic profiling including tumor mutation burden (TMB) quantification plus targeted transcriptomics for immune microenvironment and cancer cell signaling scores.

In total, 328 GC patients were enrolled. HER2-positive GC and high PD-L1 CPS were more frequent in Europe than in LATAM (9% versus 3% and 15% versus 3%, respectively), whereas EBV was mainly found in LATAM (7%, versus 3% in Europe), and dMMR/MSI tumors were equally distributed (16%). High TMB was enriched in dMMR/MSI and EBV tumors. Mutations in homologous recombination repair (HRR) genes were frequent in both cohorts (24.8% and 14.7% in Europe and LATAM, respectively), and mostly found in dMMR/MSI (63.6%) and intestinal HER2-negative (18.7%) tumors. The prognosis was poor in diffuse HER2-negative GC patients, whose tumors presented an immunosuppressive microenvironment and other distinct pathway activation signatures.

Our findings relate specific molecular alterations of GC tumors from Europe and LATAM to actionable biomarkers for precision cancer therapies. The proposed GC stratification can be implemented in routine care and guide drug development strategies.

Gastric cancer (GC) is among the most lethal malignancies worldwide. Due to the substantial heterogeneity of GC, more accurate molecular typing systems are desperately required to enhance the prognosis of GC patients.

The major immune cell subclusters in GC were identified by a single-cell RNA sequencing (scRNA-seq) dataset. High-dimensional weighted gene coexpression network analysis (hdWGCNA) and multiple bioinformatics methods were utilized to classify the molecular subtypes of GC and further investigate the differences among the subtypes. Based on the module genes and differentially expressed genes (DEGs), random survival forest analysis was applied to identify the key prognostic genes for GC, and the roles and functional mechanisms of the key genes in GC were explored by clinical samples and cellular experiments.

Two distinct GC molecular subtypes (C1 and C2) associated with neutrophils were identified, with C1 associated with better prognosis. Compared with C2 subtype, C1 subtype has significant differences in immune infiltration, immune checkpoint expression, signaling pathway regulation, tumor mutation burden, and immunotherapy and chemotherapeutic drug sensitivity. Three new key genes (VIM, RBMS1 and RGS2) were revealed to be highly correlated with the prognosis of GC patients. In addition, the expression and cellular functions of key genes RBMS1 and RGS2 in gastric carcinogenesis were verified.

We identified two neutrophil-related molecular GC subtypes with different prognostic outcomes and clinical significance. VIM, RBMS1 and RGS2 were identified as potential prognostic markers and therapeutic targets for GC. These findings provide a new perspective for the molecular typing and personalized treatment of GC.

Cancers represent a significant global health burden, affecting millions of individuals each year [...].

To develop and validate a deep learning model based on nnU-Net combined with radiomics to achieve autosegmentation of gastric cancer (GC) and preoperative prediction via the Lauren classification.

Patients with a pathological diagnosis of GC were retrospectively enrolled in three medical centers. The nnU-Net autosegmentation model was developed using manually segmented datasets and evaluated by the Dice similarity coefficient (DSC). The CT images were processed by the nnU-Net model to obtain autosegmentation results and extract radiomic features. The least absolute shrinkage and selection operator (LASSO) method selects optimal features for calculating the Radscore and constructing a radiomic model. Clinical characteristics and the Radscore were integrated to construct a combined model. Model performance was evaluated via the receiver operating characteristic (ROC) curve.

A total of 433 GC patients were divided into the training set, internal validation set, external test set-1, and external test set-2. The nnU-Net model achieved a DSC of 0.79 in the test set. The areas under the curve (AUCs) of the internal validation set, external test set-1, and external test set-2 were 0.84, 0.83, and 0.81, respectively, for the radiomic model; and 0.81, 0.81, and 0.82, respectively, for the combined model. The AUCs of the radiomic and combined models showed no statistically significant difference (p > 0.05). The radiomic model was selected as the optimal model.

The nnU-Net model can efficiently and accurately achieve automatic segmentation of GCs. The radiomic model can preoperatively predict the Lauren classification of GC with high accuracy.

This study highlights the potential of nnU-Net combined with radiomics to noninvasively predict the Lauren classification in gastric cancer patients, enhancing personalized treatment strategies and improving patient management.

The Lauren classification influences gastric cancer treatment and prognosis. The nnU-Net model reduces doctors' manual segmentation errors and workload. Radiomics models aid in preoperative Lauren classification prediction for patients with gastric cancer.

In recent years, the global prevalence of gastric cancer (GC) has witnessed a progressive decrease, accompanied by a step-growth in the incidence of gastric signet ring cell carcinoma (GSRCC). As precision medicine concepts progress, GSRCC, a distinct sub-type of GC, has drawn considerable attention from researchers. However, there still persist some controversies regarding the associated research findings.

To summarize the current obstacles and potential future directions for research on GSRCC.

To begin with, all literature related to GSRCC published from January 1, 2004 to December 31, 2023 was subjected to bibliometric analysis in this article. Additionally, this paper analyzed the research data using CiteSpace, GraphPad Prism v8.0.2, and VOSviewer, which was obtained from the Web of Science Core Collection database. The analysis results were visually represented.

This study provided a comprehensive overview of the statistical characteristics of the 995 English articles related to GSRCC, including cited references, authors, journals, countries, institutions, and keywords. The popular keywords and clusters contain "prognosis", "survival", "expression", "histology", and "chemotherapy".

The prognosis, precise definition and classification, as well as chemoresistance of GSRCC, continue to be crucial areas of ongoing research, whose directions are closely tied to advancements in molecular biology research on GSRCC.