BACKGROUND:Peritoneal metastasis (PM) is one of the most challenging clinical problems in gastric cancer (GC), largely due to its high recurrence rate and poor response to current therapies. Increasing evidence indicates that remodeling of the extracellular matrix (ECM) plays an important role in therapeutic failure. However, how specific stromal-immune interactions contribute to PM heterogeneity and immunotherapy resistance remains unclear. In this study, we investigated how ECM composition-particularly the accumulation of hyaluronic acid (HA)-influences the immune microenvironment and therapeutic responses in GC-associated PM. METHODS:We combined histopathological assessment, analyses of patient-derived specimens, single-cell transcriptomic profiling, and murine models of PM to delineate ECM remodeling patterns and immune cell dynamics in therapy-sensitive and therapy-resistant lesions. In addition, functional assays and pharmacological approaches were used to examine HA-CD44 signaling and its impact on CD4+ T cell differentiation and responsiveness to immune checkpoint blockade. RESULTS:Therapy-sensitive PM lesions were characterized by enrichment of elastic fibers, whereas therapy-resistant lesions showed collagen accumulation. Notably, HA deposition emerged as a key feature distinguishing these ECM states and was closely associated with differential therapeutic outcomes. Elevated HA levels activated CD44-dependent signaling in CD4+ T cells, driving regulatory T cell (Treg) differentiation through a CD44-IQGAP1-RAC1-SMAD3 signaling pathway and thereby establishing an immunosuppressive microenvironment. Importantly, pharmacological inhibition of CD44 reduced Treg expansion and markedly enhanced the antitumor efficacy of anti-PD-1 therapy in murine PM models. CONCLUSIONS:Our findings identify HA-CD44 signaling as a critical link between ECM remodeling and immune evasion in GC PM. Targeting ECM-driven immunosuppressive mechanisms may represent a promising strategy to overcome therapeutic resistance and improve the efficacy of immunotherapy in this aggressive disease.

BACKGROUND:The long-term survival outcomes for patients with clinical stage I gastric cancer who undergo laparoscopic total gastrectomy (LTG) are still uncertain due to the limited high-level clinical evidence. MATERIAL AND METHODS:The CLASS02 study was designed as a prospective, multicenter, open-label, randomized, non-inferiority clinical trial carried out across 14 gastroenterology centers in China. Patients diagnosed with clinical stage I gastric adenocarcinoma located in the middle and/or upper third of the stomach were randomly assigned to receive either LTG or open total gastrectomy (OTG) accompanied by D1+/D2 lymphadenectomy performed by skilled surgeons. Building on the primary analysis of safety results at 30 days, published in 2020, this extended analysis aimed to evaluate 5-year overall survival (OS) and disease-free survival (DFS) rates between LTG and OTG. RESULTS:Of the 227 patients who were enrolled between January 2017 and September 2018, 214 patients underwent total gastrectomy: 105 (49.0%) in the LTG group and 109 (51.0%) in the OTG group. The 5-year OS rate was 93.3% in the LTG group compared to 94.5% in the OTG group, and the 5-year DFS rate was 92.4% in the LTG group compared to 93.6% in the OTG group. There were no significant differences between the groups. CONCLUSION:Given the current underpowered long-term follow-up findings, LTG with D1 +/D2 lymphadenectomy performed by experienced surgeons showed numerically similar 5-year overall survival and disease-free survival rates to OTG in patients with clinical stage I gastric cancer.

Objective To explore the predictive role of pathological risk score of gastric cancer(PRSGC)in the prognosis of gastric cancer patients,and to further investigate the correlation between PRSGC and tumor biological behavior.Methods Clinicopathological data were retrospectively collected from 1 120 patients with gastric cancer who underwent surgical resection at Zhongshan Hospital,Fudan University,between April 2006 and November 2019.PRSGC was calculated using the previously established DeepRisk model,and patients were divided into high and low PRSGC groups(560 patients per group)based on the median PRSGC value.The proportions and spatial distances of immune cell subsets in gastric cancer tissues were assessed between the two groups.Data from stomach adenocarcinoma samples in The Cancer Genome Atlas was integrated to analyze PRSGC-associated genetic mutations and signaling pathways.Results The survival rate of the high PRSGC group was lower than that of the low PRSGC group,and the recurrence rate was higher than that of the low PRSGC group(P<0.000 1).Compared with the low-PRSGC group,the high-PRSGC group exhibited increased infiltration of regulatory T cells(Tregs)and neutrophils within the tumor region(P＜0.05),while the infiltration levels of natural killer T cells and cytotoxic T cells were markedly decreased(P＜0.05).Spatial analysis revealed that a shortened spatial distance between CD4+T cells and Tregs was closely associated with poor prognosis in the high-PRSGC group(P=0.03).Furthermore,in the high-PRSGC group,the number of TIM3+cells showed a positive correlation with the infiltration levels of Tregs(r=0.69,P=0.01),CD8+T cells(r=0.61,P=0.04),and CD4+T cells(r=0.67,P=0.02).Gene set enrichment analysis indicated that a high PRSGC was associated with the activation of pathways related to actin cytoskeleton regulation,the cGMP-PKG pathway,the Hippo pathway,and tumor proteoglycans.Conclusion A high PRSGC is associated with an immunosuppressive tumor microenvironment,as well as tumor invasion and metastasis.It effectively predicts the prognosis of patients with gastric cancer and,by doing so,provides a potential theoretical basis for developing individualized strategies that combine targeted therapy with immunotherapy.

Although perioperative immunotherapy has shown promising results in locally advanced gastric adenocarcinoma (LAGA), the predictive biomarkers remain unclear. Our study aimed to investigate the predictive value of [18F]FDG PET/CT characteristics at baseline for the efficacy of neoadjuvant immunotherapy plus concurrent chemoradiotherapy in the post hoc analysis of the Neo-PLANET phase II trial. A total of 29 patients with LAGA receiving neoadjuvant immunotherapy plus concurrent chemoradiotherapy from the Neo-PLANET phase II trial (Zhongshan Hospital Fudan University, NCT03631615, 2018-08-13) were included in our study. Semiautomated techniques were used to analyze pre-operative [18F]FDG PET/CT images to determine primary tumor, nodal metabolic and spleen parameter scores [including max and mean adjusted for lean body mass standardized uptake values (SUV), metabolic tumour volume (MTV) and total lesional glycolysis (TLG)]. Kaplan–Meier method and log-rank test to evaluate the associations between PET/CT parameters and disease-free survival (DFS) and overall survival (OS). Pathological complete response (pCR) and major pathological response (mPR) were not related to DFS and OS in patients receiving neoadjuvant immunotherapy plus concurrent chemoradiotherapy. Interestingly, a higher SUVmean of the spleen (S-SUVmean) is positively associated with longer DFS (HR = 0.19, 95

Background and Aim: Lymphovascular invasion (LVI) is a negative prognostic factor for gastric cancer, but detection limitations hinder its clinical utility and subtype analysis. This study aimed to explore the predictive value of LVI and its subtypes in the prognosis and recurrence patterns of gastric cancer using our enhanced detection method. Methods: We reviewed 2057 patients who underwent gastrectomy in 2018, of whom 1073 met the inclusion criteria. Propensity score matching (PSM) was performed to balance baseline clinicopathological characteristics. Results: After PSM, 311 patients were assigned to the LVI+ group and 311 to the LVI- group. The LVI+ group demonstrated a poorer prognosis. Subtype analysis revealed that lymphatic invasion (LI), but not venous invasion (VI), was associated with poor prognosis in the matched cohort. Stratified by pathological tumor-node-metastasis (TNM) stage, LVI+ and LI+ patients had worse prognosis in Stages I and III, while VI+ patients had worse prognosis in Stage III. Stratified by lymph node status, LVI+ predicted poorer prognosis in both node-negative (N0) and node-positive (N+) patients, and LI+ was also associated with worse prognosis among N+ patients, whereas VI+ was not significantly associated with prognosis in either subgroup. Recurrence analysis indicated that LVI+ was associated with distant and peritoneal metastases, whereas LI+ was associated with local recurrence, distant and peritoneal metastases. Conclusions: Lymphovascular invasion was associated with adverse prognosis in resectable gastric cancer, with lymphatic invasion showing a stronger prognostic impact than venous invasion. These findings indicate that refined assessment of lymphovascular invasion may complement conventional TNM staging in postoperative risk stratification.

Background: Immune checkpoint inhibitor (ICI)-based strategies have become a consensus in the preoperative treatment of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC). However, the necessity and optimal strategy of combining ICIs with chemotherapy remain uncertain. Methods: This retrospective study aimed to evaluate the efficacy of different preoperative chemo-immunotherapy combinations in patients with dMMR/MSI-H GC. According to their therapeutic regimens, patients were divided into three cohorts: ICI-alone cohort; immunotherapy with induction chemotherapy (IC) cohort (ICI + IC): 1-2 cycles of IC followed by ICI; concurrent chemoimmunotherapy cohort (ICI + chemo): ICI combined with chemotherapy throughout the entire preoperative treatment. The pathological complete response (pCR) rate and major pathological response (MPR) rate were analyzed. Peripheral blood parameters before and after preoperative treatment were analyzed. Results: A total of 45 patients with locally advanced or oligometastatic dMMR/MSI-H GC were included. Baseline characteristics were well balanced among the three cohorts. The pCR rates were 18.2% (95% CI, 2.3-51.8%) in the ICI-alone cohort, 85.7% (95% CI, 42.1-99.6%) in the ICI + IC cohort, and 37.0% (95% CI, 19.4-57.6%) in the ICI + chemo cohort. Notably, the ICI + IC cohort showed a significantly higher pCR rate than the other two cohorts (p=0.015). The MPR rates were 54.5%, 85.7%, and 48.1% in the three cohorts, respectively, with no statistical significance. After preoperative treatment, monocyte-to-lymphocyte ratio exhibited an upward trend in the ICI + IC (p=0.100) and ICI + chemo (p=0.058) cohorts, indicating enhanced antigen presentation activity and immune activation. Conclusion: A preoperative strategy of IC followed by ICIs significantly increased pCR rate compared to ICI monotherapy or concurrent chemo-immunotherapy, suggesting a more effective strategy for patients with resectable dMMR/MSI-H GC. Given its retrospective design, small sample size, and lack of safety data, this study warrants validation in prospective clinical trials.

Abstract Background: Treatment strategies for advanced gastric cancer (GC) largely depend on the presence or absence of metastasis. However, a subset of patients with limited metastasis may still derive meaningful benefit from curative-intent surgery, challenging the traditional binary staging paradigm. Current assessments of metastasis rely on lesion volume and anatomical distribution, which oversimplify tumor biology. The degree to which patients with metastatic GC can benefit from surgery remains unclear. We therefore propose a serum-derived staging model that integrates systemic tumor-host interactions to define biological tumor stage and inform surgical decision-making in a biologically informed manner. Methods: Advanced GC was stratified by metastatic burden into locally advanced GC (LAGC), limited metastatic GC (LMGC), and widely metastatic GC (WMGC). Cohort 1 included 179 patients receiving curative-intent surgery following preoperative systemic therapy (100 LAGC, 48 LMGC, 31 WMGC). Serum samples were obtained at baseline and preoperatively. Cohort 2, an independent dataset collected during a different period, included 149 patients (109 LAGC, 25 LMGC, 15 WMGC) with baseline serum samples. Systemic inflammatory profiles were characterized via Olink platform. Baseline samples from Cohort 1 served as the training set. Feature selection was performed using ordinal logistic regression, XGBoost, and SVM-RFE, followed by Elastic Net regression for model construction. Preoperative samples from Cohort 1 were used for internal validation, and Cohort 2 for external validation. Results: Three inflammatory proteins, IL-22 RA1, HGF, and 4E-BP1, were significantly associated with metastatic burden and were incorporated into the tumor-induced perturbation score (TIPscore). Baseline TIPscore distinguished WMGC, the subgroup least likely to benefit from surgery, from LAGC and LMGC with an AUC of 0.812. Lower TIPscore was associated with improved overall survival (OS) (p = 0.049). In preoperative samples from Cohort 1, TIPscore outperformed conventional M0/M1 staging, increasing 1-year OS prediction AUC from 0.683 to 0.850 in advanced GC overall, and reaching 0.875 in the LMGC subgroup. Among LMGC patients receiving curative surgery, a lower post-treatment TIPscore predicted better OS (p = 0.034) and event-free survival (EFS) (p = 0.015). TIPscore was further validated in Cohort 2, achieving an AUC of 0.810 for distinguishing WMGC from LAGC and LMGC, and 0.711 for distinguishing WMGC from LMGC. Conclusions: TIPscore is a biologically informed staging model that reframes metastatic burden as a continuous biological spectrum rather than a categorical variable. By precisely situating individual patients along this spectrum, TIPscore provides prognostic insight to guide surgical decision-making and may be particularly valuable in ambiguous clinical contexts such as LMGC. Citation Format: Yingying Wu, Zhenxin Wang, Hong Zeng, Yihong Sun, Zhaoqing Tang, Xuefei Wang. Predicting efficacy of curative-intent surgery in advanced gastric cancer: A biologically informed staging approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3769.

This study aimed to evaluate the prognostic value of plasma circulating tumor DNA (ctDNA) level in patients with resectable gastric cancer (GC). A total of 59 patients were prospectively enrolled, with their ctDNA detected and paired tumor tissue collected at various peri-operative time points. Patients with higher 1-month post-operative ctDNA levels demonstrated shorter overall survival status (hazard ratio [HR] = 5.30, p = 0.0022) and a higher risk of recurrence (HR = 3.85, p = 0.011). The model combining ctDNA with conventional serum tumor markers for GC, including carcinoembryonic antigen, carbohydrate antigen 19-9, and CA72-4, shows high predictive effectiveness for GC prognosis with an area under the curve of 0.940 (p = 0.002), which is higher than net ctDNA and other models without ctDNA. Patients with lower ctDNA levels were more likely to have positive stromal programmed cell death ligand 1 expression (p = 0.046). Additionally, DCAF4L2 mutation was identified as the crucial gene mutation in ctDNA suggesting poor prognosis of patients with GC. Overall, this study highlights that post-operative ctDNA can serve as an effective biomarker for prognostic prediction and recurrence surveillance in resectable GC.

Gastric cancer peritoneal metastasis (GCPM) typically indicates a poor clinical prognosis and is frequently observed in diffuse gastric cancer (GC) patients with CDH1 loss of function. GCPM characterized for its aggressiveness and resistance to chemotherapy, most notably paclitaxel (PTX), poses significant treatment challenges. Previously, no mouse gastric adenocarcinoma (MGA) cell lines with Trp53 (encoding mouse p53) and Cdh1 (encoding mouse E-cadherin) mutations and a high potential for peritoneal metastasis in mice have been established. Here, we derived a mouse GC cell line, called MTC, from subcutaneously transplanted mouse Trp53−/−Cdh1−/− GC organoids. Through matching the short tandem repeat profile of MTC with those in current cell banks, we verified the uniqueness of MTC. Furtherly, we confirmed the features of MTC by detecting the expression of p53, E-cadherin, and pan-CK. After long-term exposure of the original MTC line to PTX, we developed a more aggressive, PTX-resistant cell line, termed MTC-R. Compared with MTC, MTC-R demonstrated enhanced tumorigenicity and high potential for peritoneal metastasis in subcutaneous and intraperitoneal tumour models both in BALB/c nude mice and C57BL/6 J mice. Transcriptome analysis revealed the ECM‒receptor interaction pathway activation during the development of PTX resistance, and dasatinib (DASA) was identified as a potential drug targeting this pathway. DASA showed promise in ameliorating disease progression and improving overall survival in MTC-R GCPM model in C57BL/6 J mice. Overall, we established a novel MGA cell line with Trp53 and Cdh1 mutations and its PTX-resistant variant and demonstrated the efficacy of DASA in treating PTX-resistant GCPM.

Anti-HER2 monoclonal antibody (mAb) is the standard first-line therapy for advanced HER2+ gastric cancer. However, resistance to anti-HER2 therapy remains a significant clinical challenge. In this study, we identified a novel resistance mechanism to anti-HER2 therapy in gastric cancer and proposed a strategy to enhance therapeutic efficacy by activating T cells. The association between intratumoral immune cells and clinical responses to anti-HER2 therapy in gastric cancer was investigated. Peripheral blood mononuclear cells (PBMCs) were co-cultured with HER2+ gastric cancer cell lines or organoids to study NK cell responses mediated by anti-HER2 mAb. T cells were depleted or activated to assess their impact on antibody-dependent cellular cytotoxicity (ADCC), and the mechanism by which T cells influence ADCC was examined. The combinatorial effects of anti-HER2 mAb and HER2 × CD3 T cell-engaging bispecific antibody (bsAb) in gastric cancer were evaluated. A total of 35 gastric cancer patients receiving anti-HER2 mAb treatment were enrolled. A higher number of intratumoral T cells were associated with greater tumor regression and improved overall survival following anti-HER2 mAb therapy. Mechanistically, T cells, mainly CD4+ T cells, influence NK cell functional and phenotypic changes via interleukin-2 (IL-2) production. Activating T cells by HER2 × CD3 T cell-engaging bsAb enhanced the anti-tumor effects of anti-HER2 mAb in gastric cancer. Our study identified the lack of T cell help as a novel resistance mechanism to anti-HER2 mAb in gastric cancer. Enhancing T cell help via the combination of HER2 × CD3 bsAb improved the therapeutic efficacy of anti-HER2 mAb in gastric cancer.

Importance:Effective treatment of locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) cancer remains a challenge. Objective:To compare the efficacy and safety of atezolizumab plus trastuzumab plus capecitabine and oxaliplatin chemotherapy (XELOX) vs trastuzumab plus XELOX in Chinese patients with locally advanced human epidermal growth factor receptor 2 (ERBB2; formerly HER2)-positive GC or adenocarcinoma of the GEJ. Design, Setting, and Participants:This was an open-label phase 2 randomized clinical trial conducted at 8 study sites in China. Patient recruitment started on February 25, 2021, and this study is ongoing as participants are still being actively followed up. Chinese patients eligible for surgery with locally advanced ERBB2-positive GC or adenocarcinoma of the GEJ were included. Data were analyzed from March 2021 to October 2023. Interventions:Eligible patients were enrolled and randomly assigned 1:1 to perioperative treatment with either atezolizumab plus trastuzumab plus XELOX (arm A) or trastuzumab plus XELOX (arm B) for 3 neoadjuvant cycles (3 weeks per cycle) and 5 adjuvant cycles. Main Outcomes and Measures:The primary efficacy end point was the pathological complete response (pCR) rate following completion of neoadjuvant therapy and surgery. Results:In total, 42 patients were screened and randomly assigned to arm A (n = 21) or arm B (n = 21). The median (range) ages were 61 (33-72) years and 65 (49-72) years in arm A and arm B, respectively, and 39 patients (93%) were male. The pCR rate was significantly higher in arm A (8 [38%]) than arm B (3 [14%]; difference, 23.8%; 90% CI, 1.3-44.7). Age younger than 65 years, male sex, and intestinal Lauren classification were significantly associated with a better pCR rate in arm A. Median event-free survival, disease-free survival, and overall survival were not reached. Based on the same way of interpretation, major pathologic response should be statistically significantly different between the 2 arms, while other outcome measures remained not significantly different. The incidence of treatment-emergent adverse events was 100% (21 of 21) and 100% (21 of 21) in arms A and B, respectively; grade 3 or higher TEAEs, 57% (12 of 21) and 67% (14 of 21), respectively; and serious TEAEs, 29% (6 of 21) and 10% (2 of 21), respectively. Conclusions and Relevance:In this randomized clinical trial, add-on atezolizumab to trastuzumab plus XELOX therapy demonstrated promising efficacy in this patient population, and no new safety concerns were raised. Trial Registration:ClinicalTrials.gov Identifier: NCT04661150.

We report the short-term results of indocyanine green (ICG)-guided laparoscopic lymphadenectomy for gastric cancer (GC). The primary outcome is 3-year disease-free survival. In this analysis, we present short-term secondary outcomes focused on the number of lymph nodes (LNs) retrieved and the diagnostic value of fluorescent status for metastatic LNs, excluding long-term outcomes. A total of 1,006 patients are included in the per-protocol analysis. The mean number of LNs retrieved in the ICG group is significantly higher than that in the non-ICG group. The negative predictive value is 93.9% for nonfluorescent stations, and the sensitivity of ICG for detecting all metastatic LN stations is 91.6%. ICG technology is safe and feasible for laparoscopic lymphadenectomy in GC and can noticeably increase the number of LNs retrieved. Further follow-up is necessary to warrant whether ICG can improve long-term survival of GC. The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS)-11 trial has been registered at ClinicalTrials.gov as NCT04593615.

436 Background: Interventional therapy is a local intensive therapy for tumor control, often utilized in palliative treatment for solid organ tumors. Yet, its application in tumors of hollow viscera still lacks evidence. Our previous retrospective study revealed transarterial infusion chemotherapy and embolization (TAICE) not only effectively managed tumor-related hemorrhage but also exhibited a notable anti-tumor efficacy in gastric cancer. This prospective study aims to further explore the feasibility and safety of TAICE as a pre-operative therapy for locally advanced gastric cancer (LAGC). Methods: Patients diagnosed with locally advanced adenocarcinoma of stomach and gastrointestinal junction (GEJ) with no distant metastasis (cT3-4N+M0) were enrolled. They were given 4 cycles of pre-operative treatments: 2 cycles of TAICE-SOX (Oxaliplatin [85mg/m 2 transarterial infusion on Day 1] and S-1 [40/50/60mg po bid on Day 1-14]) and 2 cycles of SOX (Oxaliplatin [130mg/m 2 IV on Day 1] and S-1 [same as above]), alternately. Then, they received D2 radical gastrectomy, and 4 cycles of SOX post-operatively. In brief, the TAICE procedure was summarized into 4 steps: 1) Celiac arteriography, 2) Super-selection of tumor feeding artery (TFA), 3) Infusion chemotherapy and embolization of TFA, 4) Celiac re-arteriography to ensure the success of embolization. The primary endpoint was pathological complete response (pCR) rate. Other endpoints included major pathological response (MPR) rate, overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs). Results: Between December 2020 and June 2023, twenty patients were enrolled and all of them received TAICE. Among them, 18 (90.0%) patients received 2 cycles of TAICE. The pCR and MPR rate were 55.0% and 70.0%, respectively. The 1-year and 3-year OS rate were 100.0% and 82.6%. The 1-year and 3-year PFS rate were 90.0% and 67.3%. There was no difference in OS between the groups of high and low tumor residual rate with the threshold of 50%. Patients achieving low tumor residual rate had significantly longer PFS (NR vs. 12.17 months, p=0.018) than those with high rate after TAICE. Moreover, we divided TFA into two subtypes: dispersive and branching, depending on the vascular pattern presented in the angiography at the first cycle TAICE. Patients with dispersive TFA had higher risk of recurrence after TAICE (NR vs. 15.17 months, p=0.0264). All patients had TRAEs (vomiting, nausea, abdominal pain and fever) of grade 1 or 2 after the first cycle of TAICE. Only one patient experienced nausea of grade 3 after the second cycle of TAICE. The most common TRAEs were vomiting and nausea. Conclusions: TAICE is a promising pre-operative therapy for patients with LAGC for it displaying the satisfactory oncological effectiveness and safety profile. Clinical trial information: NCT05396326 .

Tumor cells heavily depend on proteasome-mediated protein turnover, making the proteasome an attractive therapeutic target. Clinically, proteasome inhibitors are effective against hematologic cancers but show limited success with solid tumors, and the reasons for this difference are not well understood. Activation of yes-associated protein (YAP)/TAZ, the downstream effectors of the Hippo pathway, is a key mechanism behind drug resistance in cancers. Here, we demonstrate that proteasome stress acts as an upstream signal of the Hippo pathway in solid tumor cells. When the proteasome is inhibited, RAP2 undergoes ubiquitination and becomes inactive, which in turn disrupts the RAP2–MAP4Ks–NF2–LATS1/2 signaling pathway, leading to the activation of YAP/TAZ. YAP/TAZ activation promotes cell survival and resistance to proteasome inhibitors. Conversely, blocking YAP/TAZ can overcome this resistance and restore cancer cell sensitivity to these drugs. In diffuse-type gastric cancer—an aggressive solid tumor with a poor prognosis and limited treatment options—combined inhibition of the proteasome and YAP/TAZ effectively suppresses tumor growth. Therefore, this study identifies proteasome stress as an upstream signal of the Hippo pathway and provides a mechanistic basis for combination cancer therapy.

Limited metastatic gastric cancer (lmGC) represents an intermediate disease stage, positioned between localized and widely disseminated gastric cancer, and has garnered increasing attention due to its distinct prognostic outcomes. Currently, there is no consensus on the optimal treatment approach for lmGC, raising the question of whether it should align more with the systemic treatment-focused approach used for metastatic gastric cancer or adopt a surgery-centric strategy similar to that used in localized disease. Previous studies have preliminarily explored combining systemic treatment and surgical resection to address both the primary tumor and metastatic lesions. However, these investigations have been constrained by limited evidence and yielded inconclusive findings. ROSETTE trial is an open-label, randomized phase II study designed to investigate treatment strategies for patients with limited metastatic gastric or gastroesophageal adenocarcinoma. Eligible patients, confirmed through comprehensive evaluation including radiography and laparoscopy, are randomized to receive either systemic treatment followed by surgery-centric local treatment, or systemic treatment alone. Systemic treatment combines immunotherapy with chemotherapy, while the surgery-centric local treatment utilizes a surgery-centric, multi-modality approach involving resection of both primary and metastatic tumors where feasible. For unresected or unresectable metastatic lesions, alternative local therapies are provided. The primary endpoint is the 1-year event-free survival (EFS) rate. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), extended EFS, overall survival (OS), pathologic complete response rate (pCR), major pathologic response rate (MPR), and R0 resection rate. The ROSETTE trial aims to evaluate whether systemic treatment followed by surgery-centric local treatment provides a survival advantage over the standard systemic-only approach for patients with limited metastatic gastric cancer. It seeks to build on previous research while addressing limitations such as selection bias inherent to non-randomized designs, patient recruitment challenges, and the complexities of managing surgical complications. By applying the latest evidence and a multi-modality approach, the ROSETTE trial endeavors to offer new insights into optimizing treatment strategies for patient with lmGC. NCT06468280 (Registration date: 05/28/2024).

BACKGROUND:The multicentre RESOLVE trial examined the efficacy of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in gastric or gastro-oesophageal junction cancer. Initial analyses did not encompass overall survival owing to the immature data. This paper provides an updated analysis of the survival data from the RESOLVE trial. METHODS:In this randomised, open-label, phase 3 study, participants aged 18 years or older with cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma who were feasible for D2 lymphadenectomy and had a Karnofsky performance score of 70 or higher were enrolled. Participants were randomly assigned in a 1:1:1 ratio via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral capecitabine 1000 mg/m2 twice a day on days 1-14, adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40-60 mg twice a day on days 1-14), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy. The primary endpoint, assessed in the modified intention-to-treat population, was 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-CapOx and the non-inferiority (hazard ratio [HR] non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx, and has been reported previously. This final report focuses on the secondary endpoint of 5-year overall survival, also assessed in the modified intention-to-treat population. Other secondary endpoints-R0 resection rate and safety-were not updated in this analysis. The study is registered at ClinicalTrials.gov, NCT01534546, and is complete. FINDINGS:Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were enrolled and randomly assigned, of whom 1022 participants were included in the modified intention-to-treat population: 345 (259 male, 86 female) in the adjuvant-CapOx group, 340 (238 male, 102 female) in the adjuvant-SOX group, and 337 (271 male, 66 female) in the perioperative-SOX group. As of April 7, 2022, the median duration of follow-up was 62·8 months (IQR 52·0-75·1). The 5-year overall survival rates were 52·1% (95% CI 46·3-57·5) for the adjuvant-CapOx group, 61·0% (55·3-66·2) for the adjuvant-SOX group, and 60·0% (54·2-65·3), for the perioperative-SOX group. Overall survival was significantly prolonged with perioperative-SOX (HR 0·79; 95% CI 0·62-1·00, p=0·049) and adjuvant-SOX (HR 0·77, 0·61-0·98, p=0·033), compared with adjuvant-CapOx. INTERPRETATION:Consistent with the initial analysis of 3-year disease-free survival, the extended 5-year overall survival analysis from the RESOLVE trial confirmed the survival advantage of perioperative-SOX and adjuvant-SOX compared with the standard adjuvant-CapOx regimen. The SOX regimen, given perioperatively or as an adjuvant treatment, emerges as a potential standard treatment modality for locally advanced gastric or gastro-oesophageal junction cancer management in Asian patients. FUNDING:The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, the Beijing Natural Science Foundation, National Natural Science Foundation of China, the Beijing Natural Science Foundation, Taiho, Hengrui Pharmaceutical and Sanofi-Aventis. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

Objective:Laparoscopic distal gastrectomy (LDG) has potential as a surgical treatment option for locally advanced gastric cancer (LAGC). However, there is uncertainty regarding the generalizability of LDG efficacy across diverse patient populations and treatment settings. This study aimed to assess the outcomes of LDG vs. open distal gastrectomy (ODG) in patients with LAGC despite differences in clinical trial populations and treatment environments. Methods:The KLASS-02 and CLASS-01 trials are multicenter, non-inferiority, open-label, randomized controlled trials for patients with LAGC eligible for distal subtotal gastrectomy in Korea and China, respectively. Some 1,050 patients were enrolled in KLASS-02, and 1,056 patients were enrolled in CLASS-01. Individual patient data (IPD) from KLASS-02 and CLASS-01 were pooled and analyzed. Results:There were 900 patients in the LDG group and 920 in the ODG group. Baseline characteristics were well balanced between groups. The LDG group had better short-term and recovery outcomes than the ODG group, although anastomotic leakage was more frequent. For patients who underwent LDG vs. ODG, 5-year overall survival (OS) was 82.7% [95% confidence interval (95% CI), 80.2%-85.2%] vs. 83.3% (95% CI, 80.9%-85.8%) (P=0.706) and 5-year recurrence-free survival (RFS) was 76.9% (95% CI, 74.1%-79.7%) vs. 77.9% (95% CI, 75.2%-80.6%) (P=0.666), respectively, with a median follow-up of 70 months. In the multivariable prognostic IPD meta-analysis, the operative approach was not independently associated with OS [hazard ratio (HR)=1.045, 95% CI, 0.833-1.311; P=0.706] or RFS (HR=1.044, 95% CI, 0.859-1.269; P=0.667) for LDG vs. ODG. In the subgroup analysis, LDG demonstrated a significant association with poorer RFS in the pT4 subgroup (HR=1.377, 95% CI, 1.022-1.760; P=0.034). Conclusions:Despite differences in patient populations, surgical practices, and postoperative treatments between trials, LDG is oncologically safe with the benefit of being minimally invasive for patients with LAGC, except for the pT4 patients. Therefore, LDG could be a good treatment alternative for patients with LAGC; however, caution should be warranted in its application for patients classified as T4.

Background:The impact of adjuvant chemotherapy (ACT) on gastric cancer (GC) patients receiving neoadjuvant chemotherapy (NACT) remains unclear. This study aims to evaluate the effect of ACT on survival in patients undergoing curative surgery after NACT. Methods:Clinical and pathological data of GC patients treated with NACT followed by radical surgery were retrospectively collected. Patients were categorized according to ACT administration. Propensity score matching (PSM) was employed to compare the prognosis between those who received ACT and those who did not. Results:After cohort selection and PSM, 180 patients with locally advanced GC were included: 116 in the ACT group and 64 in the no ACT group. No significant difference in overall survival (OS) was observed between the two groups (P=0.46). Subgroup analyses based on tumor invasion depth, lymph node metastasis, histological subtype, lymphovascular invasion (LVI), perineural invasion (PNI), and tumor regression grade (TRG) revealed no significant OS benefit from ACT in any subgroup. In a smaller cohort subset, among patients lacking mature tertiary lymphoid structures (mTLSs) in the tumor bed, the ACT group exhibited a higher OS rate compared with the no ACT group (P=0.006). Conversely, among patients with mTLSs, the no-ACT group demonstrated better survival (P=0.02). Likelihood ratio tests and multivariate Cox regression analysis indicated that the effect of ACT on OS depends on mTLS status. In subgroups stratified by mTLS status, ACT was identified as an independent prognostic factor. Conclusions:For patients with locally advanced GC treated with NACT, ACT does not confer a significant survival benefit in the overall population. The presence of mTLSs following NACT serves as a strong predictive biomarker for ACT efficacy. Patients without mTLSs in the tumor bed after NACT may derive greater benefit from ACT.

Purpose:The objective of this study was to ascertain the safety of laparoscopic distal D2 radical gastrectomy in treating gastric cancer patients after NAC with locally advanced disease (cT3-4a, N0/ +, M0) by evaluating postoperative complications. Study Design:A prospective, multicenter, single-arm clinical trial. Methods:This clinical trial was conducted at 14 hospital centers in China. Adults aged 18-75 years with histologically confirmed LAGC (cT3-4a, N0/ +, M0) were enrolled in the study. Participants received three cycles of administration of intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) plus oral capecitabine (1000 mg/m2 twice daily on days 1 to 14 of each cycle), repeated every three weeks prior to undergoing laparoscopic distal gastrectomy. The primary endpoint was the postoperative overall morbidity rate. Secondary endpoints included postoperative mortality rate, surgery-related complications, R0 resection rate, and the rate of conversion to laparotomy, response of neoadjuvant chemotherapy (NAC), adverse event rate of NAC, operation time, blood loss, postoperative severe morbidity rate, and postoperative recovery course. Results:A total of 153 patients who underwent NAC prior to laparoscopic D2 distal gastrectomy were included in the final analysis. The study reported a postoperative overall morbidity rate of 20.9% (95%CI: 15.2%-28.0%), with a postoperative mortality rate of 0%. Pneumonia is the most common complication (9.2%). Ten patients exhibited elevated levels of body fluid amylase without presenting any clinical symptoms or undergoing additional clinical intervention. The R0 resection rate was achieved at 100%. The rate of conversion to laparotomy was 1.3%. 9.2% of patients achieved pathological complete response (pCR) following NAC. The overall incidence of adverse effects after NAC was 20.3% (95%CI: 14.7%-27.3%). The most common grade 3-4 treatment-related adverse events during neoadjuvant treatment were a decrease in platelet count and vomiting, each occurring in 0.7% of patients. Conclusion:The laparoscopic distal D2 radical gastrectomy demonstrated a favorable safety profile in the treatment of gastric cancer patients with advanced disease (cT3-4a, N0/ +, M0) following NAC.