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Abstract Background Few studies have investigated the efficacy of comprehensive therapies, including immunotherapy, for gastric cancer with synchronous liver metastases (GCLM). We retrospectively compared the effect of immunochemotherapy and chemotherapy alone as conversion therapies on the oncological outcomes of patients with GCLM. Methods The clinicopathological data of 100 patients with GCLM from February 2017 to October 2021 at our institution were retrospectively analyzed. Patients were divided into immunochemotherapy (n = 33) and chemotherapy‐alone (n = 67) groups. Results Baseline clinicopathological data did not differ significantly between the two groups. The immunochemotherapy group had a higher overall response rate (59.4% vs. 44.0%, p = 0.029) and disease control rate (71.9% vs. 49.2%, p = 0.036) than the chemotherapy group. The immunochemotherapy group showed better tumor regression in the gastric mass, metastatic lymph nodes, and liver lesions than the chemotherapy group. Ten (30.3%) patients in the immunochemotherapy group and 13 (19.4%) patients in the chemotherapy group underwent surgery after conversion therapy. However, the difference was not statistically significant. The overall survival (OS) and progression‐free survival (PFS) rates were better in the immunochemotherapy group than in the chemotherapy group. Treatment‐related adverse events occurred in 24 (72.7%) and 47 (70.1%) patients in the immunochemotherapy and chemotherapy groups, respectively. Conclusions As a conversion therapy for GCLM, immunotherapy yielded better primary and metastatic tumor regression and survival benefits, with no increase in adverse events compared to chemotherapy.

Abstract Gastric cancer stem cells (GCSCs) are self‐renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA‐seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1‐CreERT2; Rosa26Tdtomato and Tff1‐CreERT2; Apcfl/fl; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest‐specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency‐induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

Abstract The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype‐related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG‐3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in‐house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPSLow is characterized as immune‐activated, and IPSHigh is immune‐silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPSLow and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti‐PD‐1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC.

Abstract Background Whether the tumor‐node‐metastasis (TNM) staging system is appropriate for patients with node‐negative gastric cancer (GC) is still inconclusive. The modified staging system developed by recursive partitioning analysis (RPA) showed good prognostic performance in a variety of cancers. The application of RPA has not been reported in the prognostic prediction of GC. Methods Node‐negative GC patients who underwent radical resection at Fujian Medical University Union Hospital (n = 862) and Sun Yat‐sen University Cancer Center (n = 311) with at least 5 years of follow‐up were selected as the training set. RPA was used to develop a modified staging system. Patients from the Surveillance, Epidemiology, and End Results database (n = 1415) were selected as the validation set. Results The 5‐year overall survival (OS) rates of patients with 8th AJCC‐TNM stage IA‐IIIA in the training set were IA 95.2%, IB 87.1%, IIA 78.3%, IIB 75.8%, and IIIA 72.6%. Multivariate analysis (MVA) showed that larger tumor size, elder age, and deeper depth of invasion were independent predictors for OS in patients with node‐negative GC (all P

Abstract Background Little is known about the correlation between the clinicopathological features, postoperative treatment, and prognosis of multiple gastric cancers (MGCs). In this study, we aimed to investigate the correlation between these features and the impact of postoperative adjuvant chemotherapy on the long-term survival of patients with MGC. Methods The clinical and pathological data of patients diagnosed with gastric adenocarcinoma who had radical gastrectomy from January 2007 to December 2016 were analyzed. Using propensity score matching, the prognostic differences, and the impact of postoperative adjuvant chemotherapy between those with MGC and solitary gastric cancers (SGC) were compared. Results Among the 4107 patients investigated, the incidence of MGC was 3.2% (133/4107). Before matching, patients with MGC and SGC had disparities in the type of gastrectomy, pathological tumor stage (pT), pathological node stage (pN), and pathological tumor-node-metastasis stage (pTNM). After a 1:4 ratio matching, the clinical data of 133 cases of MGC and 532 cases of SGC were found to be comparable. The 5-year overall survival (OS) rate was 56.6% in the entire matched cohort, 48.1% in the MGC group, and 58.7% in the SGC group (P = 0.013). Multivariate analysis revealed that MGC, age, pT stage, pN stage, and adjuvant chemotherapy were independent predictors of OS (all P

Abstract Given the rarity and indolent clinical course of gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), conditional survival might be the most suitable parameter for cancer survivors who wish to receive accurate prognostic information during follow‐up. We have explored the updated incidence trend and the conditional survival of patients with GEP‐NETs. Incidence trends from 2000 to 2014 were determined through an assessment of patients in the SEER cancer registry. Patients diagnosed between 1988 and 2011 were included in the conditional survival analysis, and the 3‐year conditional cancer‐specific survival (CCS3) was computed. The incidence of GEP‐NETs, which is far higher than the incidence of many malignant tumors, is still increasing steadily (annual percentage change = 4.4). The risk of death from NETs is dynamic over time, and most deaths occur in the first 3 years after diagnosis. Patients with gastric, rectal, or appendiceal NETs hardly exhibit any excess mortality (CCS3 > 95%) given that they have already survived until a defined time‐point within 10 years. The initial difference between each age group basically disappeared with an extension of the survival time since the initial diagnosis of gastric, appendiceal, or rectal NETs, but the difference persisted for tumors at other sites. Although patients with advanced‐stage or higher‐grade tumors have a worse survival at diagnosis than patients with early‐stage or lower‐grade tumors, the difference diminishes and might even disappear over time. For GEP‐NETs that are rare but exhibit slow growth, clinically relevant variations in conditional survival were observed based on the time since diagnosis. Therefore, conditional survival can serve as a guideline that can be used by cancer survivors to plan their future and doctors to plan surveillance schedules.