Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.

BACKGROUND: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. METHODS: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). RESULTS: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. CONCLUSION: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.

Is there any difference between Eastern and Western clinical practice guidelines in management of gastric cancer?

BACKGROUND AND RECENT FINDINGS: Gastric cancer (GC) has been known as one of the most common causes of cancer mortality both in Western and Eastern countries. However, there might be differences between how it is managed in different countries. Thus, we aimed to investigate these differences. MATERIALS AND METHODS: The most well-known clinical guidelines in field of GC management including Korean GC Association (KGCA), Japanese GC Association (JGCA), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), British Society of Gastroenterology (BSG), and National Institute for health and Care Excellence (NICE) have been reviewed. RESULTS: The contents of these guidelines were categorized under eight headings including (1) genetic predisposition, (2) prevention, (3) management of gastric polyp, atrophy, dysplasia and metaplasia, (4) diagnosis, (5) pathology and molecular biology, (6) treatment, (7) supportive and palliative care, and (8) follow up. Difference in each section was discussed. CONCLUSION: Considering KGCA and JGCA as Eastern and NCCN, ESMO, BSG, and NICE as Western guidelines, it is revealed that both sets of guidelines share common practices such as prioritizing comprehensive diagnostic evaluations, personalizing treatment plans, and palliative care. However, main differences can be seen in treatment regimens, the adoption of newer therapies like immunotherapy, and the utilization of emerging techniques such as HIPEC. These differences reflect the diverse clinical landscapes, research focuses, and healthcare systems within these regions.

Neoadjuvant immunotherapy improves outcomes for resectable gastroesophageal junction cancer: A systematic review and meta-analysis.

BACKGROUND: In recent years, neoadjuvant immunotherapy (NAIT) has developed rapidly in patients with gastroesophageal junction cancer (GEJC). The suggested neoadjuvant treatment regimens for patients with GEJC may vary in light of the efficacy and safety results. METHODS: A search of the Cochrane Library, PubMed, Embase, and Web of Science was completed to locate studies examining the safety and effectiveness of NAIT for resectable GEJC. We analyzed the effect sizes (ES) and 95% confidence intervals (CI) in addition to subgroups and heterogeneity. Meta-analyses were performed using Stata BE17 software. RESULTS: For these meta-analyses, 753 patients were chosen from 21 studies. The effectiveness of NAIT was assessed using the pathological complete response (pCR), major pathological response (MPR), and nodal downstage to ypN0 rate. The MPR, pCR, and nodal downstage to ypN0 rate values in NAIT were noticeably higher (MPR: ES = 0.45; 95% CI: 0.36-0.54; pCR: ES = 0.26; 95% CI: 0.21-0.32; nodal downstage to ypN0 rate: ES = 0.60; 95% CI: 0.48-0.72) than those of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) (MPR < 30%; pCR: ES = 3%-17%; nodal downstage to ypN0 rate: ES = 21%-29%). Safety was assessed using the treatment-related adverse events (trAEs) incidence rate, surgical delay rate, surgical complications incidence rate, and surgical resection rate. In conclusion, the incidence of trAEs, incidence of surgical complications, and surgical delay rate had ES values of 0.66, 0.48, and 0.09, respectively. These rates were comparable to those from nCT or nCRT (95% CI: 0.60-0.70; 0.15-0.51; and 0, respectively). The reported resection rates of 85%-95% with nCT or nCRT were comparable to the mean surgical resection rate of 90%. CONCLUSION: NAIT is an effective treatment for resectable GEJC; additionally, the level of NAIT toxicity is acceptable. The long-term effects of NAIT require further study.

New genetic insights into immunotherapy outcomes in gastric cancer via single-cell RNA sequencing and random forest model.

OBJECTIVE: The high mortality rate of gastric cancer, traditionally managed through surgery, underscores the urgent need for advanced therapeutic strategies. Despite advancements in treatment modalities, outcomes remain suboptimal, necessitating the identification of novel biomarkers to predict sensitivity to immunotherapy. This study focuses on utilizing single-cell sequencing for gene identification and developing a random forest model to predict immunotherapy sensitivity in gastric cancer patients. METHODS: Differentially expressed genes were identified using single-cell RNA sequencing (scRNA-seq) and gene set enrichment analysis (GESA). A random forest model was constructed based on these genes, and its effectiveness was validated through prognostic analysis. Further, analyses of immune cell infiltration, immune checkpoints, and the random forest model provided deeper insights. RESULTS: High METTL1 expression was found to correlate with improved survival rates in gastric cancer patients (P = 0.042), and the random forest model, based on METTL1 and associated prognostic genes, achieved a significant predictive performance (AUC = 0.863). It showed associations with various immune cell types and negative correlations with CTLA4 and PDCD1 immune checkpoints. Experiments in vitro and in vivo demonstrated that METTL1 enhances gastric cancer cell activity by suppressing T cell proliferation and upregulating CTLA4 and PDCD1. CONCLUSION: The random forest model, based on scRNA-seq, shows high predictive value for survival and immunotherapy sensitivity in gastric cancer patients. This study underscores the potential of METTL1 as a biomarker in enhancing the efficacy of gastric cancer immunotherapy.

Integrated multi-omics analysis and machine learning identify hub genes and potential mechanisms of resistance to immunotherapy in gastric cancer.

BACKGROUND: Patients with gastric cancer respond poorly to immunotherapy. There are still unknowns about the biomarkers associated with immunotherapy sensitivity and their underlying molecular mechanisms. METHODS: Gene expression data for gastric cancer were gathered from TCGA and GEO databases. DEGs associated with immunotherapy response came from ICBatlas. KEGG and GO analyses investigated pathways. Hub genes identification employed multiple machine algorithms. Associations between hub genes and signaling pathways, disease genes, immune cell infiltration, drug sensitivity, and prognostic predictions were explored via multi-omics analysis. Hub gene expression was validated through HPA and CCLE. Multiple algorithms pinpointed Cancer-Associated Fibroblasts genes (CAFs), with ten machine-learning methods generating CAFs scores for prognosis. Model gene expression was validated at the single-cell level using the TISCH database. RESULTS: We identified 201 upregulated and 935 downregulated DEGs. Three hub genes, namely CDH6, EGFLAM, and RASGRF2, were unveiled. These genes are implicated in diverse disease-related signaling pathways. Additionally, they exhibited significant correlations with disease-associated gene expression, immune cell infiltration, and drug sensitivity. Exploration of the HPA and CCLE databases exposed substantial expression variations across patients and cell lines for these genes. Subsequently, we identified CAFs-associated genes and established a robust prognostic model. The analysis in the TISCH database showed that the genes in this model were highly expressed in CAFs. CONCLUSIONS: The results unveil an association between CDH6, EGFLAM, and RASGRF2 and the immunotherapeutic response in gastric cancer. These genes hold potential as predictive biomarkers for gastric cancer immunotherapy resistance and prognostic assessment.

A degradome-related signature for predicting the prognosis and immunotherapy benefit in stomach adenocarcinoma based on machine learning procedure.

Stomach adenocarcinoma (STAD) is one of the subtype of gastric cancer with high invasiveness, extreme heterogeneity, high morbidity, and high mortality. The degradome is the most abundant class of cellular enzymes that play an essential role in regulating cellular activity and carcinogenesis. An integrative machine learning procedure including 10 methods was performed to develop a prognostic degradome-based prognostic signature (DPS) in TCGA, GSE15459, GSE26253, and GSE62254 datasets. Investigations of the DPS concerning immune infiltration, immunotherapy benefits, and drug priority were orchestrated. The DPS developed by Enet [alpha = 0.3] method was regarded as the optimal prognostic model. The DPS had a stable and powerful performance in predicting the clinical outcome of STAD and served as an independent risk factor in training and testing cohorts. The C-index of DPS was higher than that of age, sex, and clinical stage. STAD patients with low DPS scores had a higher abundance of B cells, CD8+ T cells, higher cytolytic scores, and T cell co-stimulation scores. Moreover, low DPS score indicated a lower tumor immune dysfunction and exclusion score, lower T cell dysfunction and exclusion score, higher PD1&CTLA4 immunophenoscore, and higher tumor mutation burden score in STAD, demonstrating a better immunotherapy response. STAD patients with a high DPS score had a lower IC50 value of common chemotherapy and targeted therapy regimens (Cisplatin, Docetaxel, Gefitinib, etc). Our study developed an optimal DPS for STAD. The DPS could predict the prognosis, risk stratification and guide treatment for STAD patients.

Marital Self-Disclosure Intervention for the Fear of Cancer Recurrence in Chinese Patients With Gastric Cancer: Protocol for a Quasiexperimental Study.

BACKGROUND: Patients with gastric cancer experience different degrees of fear of cancer recurrence. The fear of cancer recurrence can cause and worsen many physical and psychological problems. We considered the "intimacy and relationship processes in couples' psychosocial adaptation" model. OBJECTIVE: The study aims to examine the effectiveness of a marital self-disclosure intervention for improving the level of fear of cancer recurrence and the dyadic coping ability among gastric cancer survivors and their spouses. METHODS: This is a quasiexperimental study with a nonequivalent (pretest-posttest) control group design. The study will be conducted at 2 tertiary hospitals in Taizhou City, Jiangsu Province, China. A total of 42 patients with gastric cancer undergoing chemotherapy and their spouses will be recruited from each hospital. Participants from Jingjiang People's Hospital will be assigned to an experimental group, while participants from Taizhou People's Hospital will be assigned to a control group. The participants in the experimental group will be involved in 4 phases of the marital self-disclosure (different topics, face-to-face) intervention. Patients will be evaluated at baseline after a diagnosis of gastric cancer and reassessed 2 to 4 months after baseline. The primary outcome is the score of the Fear of Progression Questionnaire-Short Form (FoP-Q-SF) for patients. The secondary outcomes are the scores of the FoP-Q-SF for partners and the Dyadic Coping Inventory. RESULTS: Research activities began in October 2022. Participant enrollment and data collection began in February 2023 and are expected to be completed in 12 months. The primary results of this study are anticipated to be announced in June 2024. CONCLUSIONS: This study aims to assess a marital self-disclosure intervention for improving the fear of cancer recurrence in Chinese patients with gastric cancer and their spouses. The study is likely to yield desirable positive outcomes as marital self-disclosure is formulated based on evidence and inputs obtained through stakeholder interviews and expert consultation. The study process will be carried out by nurses who have received psychological training, and the quality of the intervention will be strictly controlled. TRIAL REGISTRATION: ClinicalTrials.gov NCT05606549; https://clinicaltrials.gov/study/NCT05606549. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55102.

Real-world evidence of treatment patterns and survival of metastatic gastric cancer patients in Germany.

BACKGROUND: Patients with metastatic gastric cancer (mGC) have poor prognosis. This real-world study aimed to describe treatment regimens and survival of mGC patients. METHODS: A retrospective analysis was conducted using anonymized German claims data (AOK PLUS) covering a period from 2010 to 2021. The study population included newly diagnosed mGC cases identified from 2011 to 2020. The index date was defined as the first diagnosis of metastasis on or after gastric cancer diagnosis. Therapy regimens were identified based on inpatient and outpatient data, and subsequently stratified by line of treatment. Survival analyses were conducted using the Kaplan-Meier method. RESULTS: The cohort consisted of 5,278 mGC incident cases (mean age: 72.7 years; male: 61.9%). Nearly half of the incident cases received mGC-related treatment (49.8%). Treated patients were more often male, younger, and had fewer comorbidities compared to untreated patients. Of the 2,629 mGC patients who started the first line of treatment (1LOT), 32.8% switched to 2LOT, and 10.2% reached 3LOT. Longer survival time was observed among disease-specific treated cases compared with untreated cases (median real-world overall survival (rwOS): 12.7 months [95%CI 12.1 - 13.3 months] vs. 3.7 months [95%CI 3.4 - 4.0 months]). CONCLUSION: Systemic therapy was not received in almost half of the mGC patients. In those patients, a very short median rwOS was observed. Treatment patterns were generally in line with the guideline recommendations, however, therapy switching rates and poor prognosis indicate high unmet needs also in the treated population.

The Clinical Impact of the Prognostic Immune and Nutritional Index in Gastric Cancer Patients Who Received Curative Treatment.

BACKGROUND/AIM: The prognostic immune and nutritional index (PINI) was developed and reported as a promising prognostic factor. This study aimed to clarify the clinical impact of the PINI in gastric cancer (GC) patients who received curative treatment. PATIENTS AND METHODS: Patients who underwent curative resection for GC at Yokohama City University between 2005 and 2020 were selected based on their medical records. The PINI was calculated by dividing the serum albumin concentration (g/dl) by the serum monocyte concentration. Both measurements were performed prior to surgery. RESULTS: A total of 262 patients were included in this study. Based on the 3- and 5-year overall survival (OS), we set the cutoff value of the PINI at 3.4 in the present study. The 3- and 5-year OS rates were 69.0% and 66.1%, respectively, in the PINI-low group and 90.5% and 82.8% in the PINI-high group. There were significant differences between the two groups (p<0.001). A multivariate analysis of factors associated with OS identified PINI as an independent prognostic factor (hazard ratio=1.996; 95% confidence interval=1.096-3.636, p=0.024). Similar results were observed for RFS. In addition, the PINI status affected the recurrence pattern, postoperative anastomotic leakage, and the introduction of postoperative adjuvant chemotherapy. CONCLUSION: The PINI is a promising nutritional and inflammatory marker for patients with GC and might be a useful marker for the treatment and management of patients with GC.

Liquid biopsy for gastric cancer: Techniques, applications, and future directions.

After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist's perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.

TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy.

Introduction: The ErbB-2.1(TOB1) signaling transducer protein is a tumor-suppressive protein that actively suppresses the malignant phenotype of gastric cancer cells. Yet, TOB1 negatively regulates the activation and growth of different immune cells. Understanding the expression and role of TOB1 in the gastric cancer immune environment is crucial to maximize its potential in targeted immunotherapy. Methods: This study employed multiplex immunofluorescence analysis to precisely delineate and quantify the expression of TOB1 in immune cells within gastric cancer tissue microarrays. Univariate and multivariate Cox analyses were performed to assess the influence of clinical-pathological parameters, immune cells, TOB1, and double-positive cells on the prognosis of gastric cancer patients. Subsequent experiments included co-culture assays of si-TOB1-transfected neutrophils with AGS or HGC-27 cells, along with EdU, invasion, migration assays, and bioinformatics analyses, aimed at elucidating the mechanisms through which TOB1 in neutrophils impacts the prognosis of gastric cancer patients. Results: We remarkably revealed that TOB1 exhibits varying expression levels in both the nucleus (nTOB1) and cytoplasm (cTOB1) of diverse immune cell populations, including CD8+ T cells, CD66b+ neutrophils, FOXP3+ Tregs, CD20+ B cells, CD4+ T cells, and CD68+ macrophages within gastric cancer and paracancerous tissues. Significantly, TOB1 was notably concentrated in CD66b+ neutrophils. Survival analysis showed that a higher density of cTOB1/nTOB1+CD66b+ neutrophils was linked to a better prognosis. Subsequent experiments revealed that, following stimulation with the supernatant of tumor tissue culture, the levels of TOB1 protein and mRNA in neutrophils decreased, accompanied by enhanced apoptosis. HL-60 cells were successfully induced to neutrophil-like cells by DMSO. Neutrophils-like cells with attenuated TOB1 gene expression by si-TOB1 demonstrated heightened apoptosis, consequently fostering a malignant phenotype in AGS and HCG-27 cells upon co-cultivation. The subsequent analysis of the datasets from TCGA and TIMER2 revealed that patients with high levels of TOB1 combined neutrophils showed better immunotherapy response. Discussion: This study significantly advances our comprehension of TOB1's role within the immune microenvironment of gastric cancer, offering promising therapeutic targets for immunotherapy in this context.

[Regarding the selection of individualized therapy after neoadjuvant therapy for gastrointestinal tumors].

Gastrointestinal tumors have been widely concerned because of increasing morbidity and mortality. In the process of exploring the therapeutic patterns of gastrointestinal tumors, patients treated with neoadjuvant therapies have good effect of tumor regression and favorable prognosis. Thus, neoadjuvant therapy strategies are recommended by major guidelines of gastrointestinal tumors in the world. Meanwhile, they have a great impact on the traditional methods of surgery, the influence mainly involves the reduction of the surgical margin and the scope of lymph node dissection in gastric cancer, while involves performing organ preservation and watch & wait in selective patients with colorectal cancer. These effects and changes were based on effective control of local recurrence by neoadjuvant therapies, and the advantages of neoadjuvant therapy in terms of tumor regression and survival supported by many studies. It is also based on the patient's desire for organ preservation and non-surgical treatment. Meanwhile, application of neoadjuvant therapy strategies increase surgical difficulty and postoperative complications, but the overall impact on patient prognosis is weak. Therefore, the selection of an appropriate treatment model after neoadjuvant therapy requires an effective overall post-treatment evaluation. In particular, it is necessary to pay attention to the evaluation of imaging, endoscopy, etc., while effectively performing monitoring and follow-up, and finally establishing an appropriate salvage treatment. This article will review the status and problems of individualized treatment after neoadjuvant therapy of gastrointestinal tumor.

[Clinical significance of immune checkpoint inhibitors in neoadjuvant therapy for gastric cancer].

Multiple prospective clinical studies have demonstrated that chemotherapy combined with immune checkpoint inhibitors (ICIs) can prolong the survival of patients with far-advanced gastric cancer. For patients with locally advanced gastric cancer (LAGC), preoperative neoadjuvant chemotherapy combined with immunotherapy has also achieved some encouraging results which benefit some patients, achieve clinical downstage, attenuate hidden metastases, increase R0 resection rate and reduce postoperative recurrence rate, etc. How to apply ICIs or combine immunotherapy with other therapies correctly in the course of neoadjuvant comprehensive treatment for patients with LAGC is still a very challenging and difficult problem. There are three basic principles in immunotherapy to be grasped: (1) Based on high-level clinical practice guidelines; (2) Based on the results of high-quality evidence-based medical research; and (3) Based on molecular pathology and tumor biomarkers. Perioperative immunotherapy for gastric cancer can be correctly applied if these three principles are organically integrated. Referring to the results of domestic and international clinical research in recent years, the three basic principles are demonstrated in this article for readers.

[The efficacy and safety of laparoscopic radical gastrectomy after neoadjuvant chemotherapy combined with immunotherapy and targeted therapy].

Objectives: To explore the efficacy and safety of laparoscopic radical gastrectomy after neoadjuvant chemotherapy combined with immunotherapy and targeted therapy in patients with gastric cancer. Methods: A retrospective analysis of clinical and pathological data of 20 patients with locally advanced gastric cancer (clinical TNM stage T3-4aN+M0) admitted to the Cancer Hospital, Chinese Academy of Medical Sciences from July 2021 to July 2023. All patients received 3 cycles of SOX (Oxaliplatin+S-1) regimen combined with immunotherapy (Trastuzumab) and targeted therapy (Apatinib) as neoadjuvant treatment followed by laparoscopic radical gastrectomy for gastric cancer. Surgical outcomes, postoperative pathological response, and postoperative recovery were observed. Quantitative data, except for age and operation time, were expressed using Median (range). Results: Among the 20 patients, there were 18 males and 2 females, aged 41 to 73 years [(60.6±9.7) years]. All 20 patients underwent laparoscopic surgical treatment after neoadjuvant therapy, with one patient undergoing laparoscopic conversion to open total gastrectomy with partial transverse colon resection due to tumor invasion into the transverse mesocolon. Eight patients underwent totally laparoscopic radical gastrectomy, all with Billroth Ⅱ+Braun anastomosis at the distal stomach. Eleven patients underwent laparoscopic-assisted radical gastrectomy, among which total gastrectomy with Roux-en-Y anastomosis was performed in ten cases, and proximal gastrectomy with esophagogastrostomy overlap anastomosis was performed in one case. The mean operation time for the 20 patients was (165.0±34.1) minutes; intraoperative blood loss was 80 (20-100) ml; and the number of lymph nodes retrieved was 68 (21-89). Postoperative pathological TNM staging revealed stage T0N0M0 in six cases, stage Ⅰ in two cases, stage Ⅱ in three cases, and stage Ⅲ in nine cases. Six patients (30.0%) achieved pathological complete response, and nine patients (45.0%) achieved significant pathological response. The median postoperative time to flatus was 4 (1-5) days; oral intake resumed after 3 (2-5) days; and the median length of hospital stay was 13 (6-19) days. One patient developed colonic anastomotic leakage with intra-abdominal infection, and one patient developed duodenal stump leakage with intra-abdominal infection, both classified as Clavien-Dindo grade 3A complications, and improved after treatment and discharged. One patient developed gastric paresis, and two patients developed pleural effusion, classified as Clavien-Dindo grade 2 complications, and improved after treatment and discharged. There were no deaths within 30 days after discharge. Conclusions: Laparoscopic radical gastrectomy for gastric cancer after neoadjuvant treatment with the SOX regimen combined with immunotherapy and targeted therapy is safe and feasible, with satisfactory short-term efficacy. However, there is an increase in overall surgical risk and difficulty, and it is recommended to be performed in experienced gastric cancer centers.

The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape.

Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an "immune-hot" phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.

Gastric neuroendocrine neoplasms.

Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger-Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients' gNETs.

Integrated analysis of single-cell and bulk RNA-sequencing reveals a novel signature based on NK cell marker genes to predict prognosis and immunotherapy response in gastric cancer.

Natural killer (NK) cells play essential roles in the tumor development, diagnosis, and prognosis of tumors. In this study, we aimed to establish a reliable signature based on marker genes in NK cells, thus providing a new perspective for assessing immunotherapy and the prognosis of patients with gastric cancer (GC). We analyzed a total of 1560 samples retrieved from the public database. We performed a comprehensive analysis of single-cell RNA-sequencing (scRNA-seq) data of gastric cancer and identified 377 marker genes for NK cells. By performing Cox regression analysis, we established a 12-gene NK cell-associated signature (NKCAS) for the Cancer Genome Atlas (TCGA) cohort, that assigned GC patients into a low-risk group (LRG) or a high-risk group (HRG). In the TCGA cohort, the areas under curve (AUC) value were 0.73, 0.81, and 0.80 at 1, 3, and 5 years. External validation of the predictive ability for the signature was then validated in the Gene Expression Omnibus (GEO) cohorts (GSE84437). The expression levels of signature genes were measured and validated in GC cell lines by real-time PCR. Moreover, NKCAS was identified as an independent prognostic factor by multivariate analysis. We combined this with a variety of clinicopathological characteristics (age, M stage, and tumor grade) to construct a nomogram to predict the survival outcomes of patients. Moreover, the LRG showed higher immune cell infiltration, especially CD8+ T cells and NK cells. The risk score was negatively associated with inflammatory activities. Importantly, analysis of the independent immunotherapy cohort showed that the LRG had a better prognosis and immunotherapy response when compared with the HRG. The identification of NK cell marker genes in this study suggests potential therapeutic targets. Additionally, the developed predictive signatures and nomograms may aid in the clinical management of GC.

A radiomics signature derived from CT imaging to predict MSI status and immunotherapy outcomes in gastric cancer: a multi-cohort study.

BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.