361 Background: Neoadjuvant chemoimmunotherapy is revolutionizing the treatment landscape for solid tumors. However, a subset of patients exhibited limited therapeutic response. Metabolomic profiling of non-responding patients revealed aberrant polyol pathway activation, with sorbitol accumulation identified as a novel immune-modulatory mechanism. To address this challenge , we initiated a randomized controlled trial evaluating the safety and efficacy of chemoimmunotherapy combined with a sorbitol-restricted diet in locally advanced gastric cancer (LAGC) patients. Methods: Key inclusion criteria were: age ≥ 18 years; histologically confirmed gastric cancer with locally advanced disease as defined by the AJCC 8th Edition; and no prior systemic anticancer therapy. Eligible patients were randomized 1:1 to receive either neoadjuvant chemoimmunotherapy (3-week cycles of SOX plus PD-1 antibody tislelizumab) combined with sorbitol-supplemented diet (2 g per dose, three times daily during treatment weeks； intervention group), or neoadjuvant chemoimmunotherapy (control group). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, disease control rate (DCR), and R0 resection rate. Exploratory endpoints included treatment-related adverse events (TRAEs), progression-free survival (PFS), and overall survival (OS). Clinical trial registration: NCT06826079. Results: This interim analysis included the first 26 patients (13 per arm) of a planned 86-patient cohort. Demographic characteristics were comparable between groups, with the investigational arm comprising 8 males and 5 females (mean age 59 years, range 45-72) and the control arm 9 males and 4 females (mean age 56 years, range 48-68). Gastric signet ring cell carcinoma (GSRCC), prevalence showed a numerical trend favoring the investigational arm (46.2% vs 30.8%, p=0.42). Both groups demonstrated identical pCR rates (23.1%, 3/13 per arm), but the investigational arm exhibited superior MPR rates (61.5% vs 38.5%, p=0.039) and significantly higher ypN0 status achievement (76.9% vs 38.5%, p=0.012), with the GSRCC subgroup showing similar trends (MPR: 50% vs 25%; ypN0: 67.7% vs 25%). Both groups maintained 100% R0 resection and DCR rate. Safety profiles were comparable, with any-grade TRAEs occurring in 53.8% (7/13) of the investigational arm and 46.2% (6/13) of controls, and grade ≥3 TRAEs in 15.4% (2/13) per arm. Diarrhea was predominant in the investigational group, while leukopenia was most frequent in controls. Conclusions: This interim analysis demonstrates that the addition of a sorbitol-supplemented diet to neoadjuvant chemoimmunotherapy significantly enhances therapeutic efficacy in LAGC patients while maintaining a comparable safety profile. Clinical trial information: NCT06826079 .

[This corrects the article DOI: 10.3892/etm.2017.4282.].

The potential for immunotherapy in patients with locally advanced gastric cancer (LAGC) is recently confirmed. To report the 3-year follow-up data are aimed from a novel clinical trial. This is a prospective single-arm phase II trial. Patients with LAGC received neoadjuvant tislelizumab plus SOX before surgery. Biopsies are obtained before treatment, and tumor samples post-treatment underwent single-cell RNA sequencing (scRNA-seq). Spatial transcriptomics is conducted for validation. Cox regression models and Kaplan-Meier analysis are applied. A total of 49 patients are enrolled, and the median progression-free (PFS) and overall survival (OS) are not achieved. The 3-year PFS and OS rates are 64.1% and 73.2%, respectively. scRNA-seq of 22, 248 cells from tumors from seven patients with LAGC enabled annotation of three cancer-associated fibroblast (CAF) phenotypes. Spatial transcriptomics of gastric cancer samples validate the classification, showing inflammatory CAFs (iCAFs) negatively correlated with immunotherapy efficacy. Patients with LAGC show a favorable prognosis after neoadjuvant tislelizumab plus SOX treatment. CAF heterogeneity is crucial for patients with gastric cancer undergoing immunotherapy, and iCAFs is associated with an immunosuppressive microenvironment during PD-1 blockade with SOX therapy and validated by in vitro experiments. Patients with LAGC with higher iCAF scores are resistant to SOX PD-1 blockade.

BACKGROUND:Disease burden of gastric cancer among senior population could not be neglected. Nevertheless, there were lacking of systemic evidences regarding specified treatments. We aimed to conduct the first network meta-analysis on this topic. METHODS:From inception to August 2025, PubMed, Web of Science, Embase, Cochrane Central and ASCO meeting library were searched for literature retrieval. Randomized controlled trials investigating relative survival outcomes of different regimens among senior gastric cancer patients were included. Risk of bias 2 (ROB2) tool was employed to assess methodological quality. Hazard ratio with 95% confidence interval was used as effect size. Overall survival was primary endpoint while event-free or progression-free survival was secondary endpoint. R software was applied to perform Bayesian network meta-analysis. RESULTS:120 trials were eligible, including at least 21 393 senior patients. Only one trial was rated as high risk of bias. Regarding resectable gastric cancer, pDuFLOT (EFS 0.43, 0.22-0.84) and pSOX (EFS 0.49, 0.31-0.76) significantly improved survival outcomes than aCAPOX. Concerning first-line regimens, CadCAPOX (OS 0.65, 0.47-0.90), SuCAPOX (OS 0.68, 0.50-0.93), PemCAPOX (OS 0.77, 0.64-0.92) and NiCAPOX (OS 0.75, 0.63-0.89) showed significantly better survival than CAPOX. Subgroup analyses on regions, HER2, PD-L1 and CLDN18.2 expression levels were also performed. Moreover, first-line maintenance, second-line, third-line or subsequent regimens among senior patients were also meta-analyzed. CONCLUSION:pDuFLOT and pSOX are potential regimens among senior patients with resectable gastric cancer. At this moment, pDuFLOT may be globally used while pSOX should better be applied among East Asian countries. CadCAPOX, SuCAPOX, PemCAPOX and NiCAPOX are considered as potential first-line regimens among HER2-negative senior patients. CadCAPOX and SuCAPOX are probably more fit for East Asian patients currently, while NiCAPOX may be better applied among Western countries and PemCAPOX has the potential of worldwide application. SuCAPOX is a potential regimen among HER2-negative/PD-L1-positive senior patients, while PemCAPOX may also be considered. Currently, standard CAPOX or FOLFOX regimen may still be available for HER2-negative senior patients with CLDN18.2, FGFR2b or MET positivity. Meanwhile, among HER2-positive senior patients, TraCAPOX is still considered to be available. Regarding first-line maintenance treatments, RamP is a potential regimen among HER2-negative or non-specific senior patients, especially those from Western countries. As second-line regimens, FruP and RamP may be potentially available among East Asian and worldwide HER2-negative senior patients respectively, while T-DXd has the potential of global application among HER2-positive counterparts. Concerning third-line or subsequent regimens, T-DXd is potentially available among HER2-positive senior patients, especially from East Asian countries. Among HER2-negative or non-specific patients, RamIRI is a potential regimen, especially among East Asian patients, while nivolumab and regorafenib may still be available at this moment. Meanwhile, nivolumab and other parallel regimens already recommended by guidelines are still potentially available among HER2-negative/CLDN18.2-positive senior patients. As the first network meta-analysis on this topic, our conclusions may not only provide potential supplements for current guidelines, but also reveal the necessity and directions for future clinical and mechanism researches, especially because of the underpowered subgroup data and exploratory nature of regional applicability.

Cancer vaccines mount specific immune memory responses and hold great potential in suppressing postoperative colorectal cancer (CRC) recurrence. However, undesired lymph node trafficking and antigen cross-presentation hamper clinical translation of nanovaccines. Here, we propose a controllable transformable nanovaccine grounded on thermal fusion feature of liquid metal (LM) nanoparticles against postoperative CRC recurrence. After draining to lymph nodes, LM-based nanovaccines (LMVs) aggregate and transform from spheres to fusiform sharp under NIR irradiation, conducive to cytoplasmic delivery of LMVs and subsequent antigen cross-presentation. Benefitting from the morphology transformation, LMVs prolong the retention of loaded vaccine molecules in lymph nodes, resulting in satisfactory dendritic cell (DC) recognition and maturation. Such dual effects of transformable LMVs efficiently activate DCs and cytotoxic CD8+ T cells, mediating strong systemic immune responses against local recurrence. Moreover, the transformable LMVs can induce potent specific immune memory, which is pivotal for eradicating metachronous liver and lung metastasis. This study provides a newly NIR light-regulated postoperative CRC prevention approach.

Purpose: This study aims to compare the efficacy of two treatment strategies for gastric cancer with clinical evidence of pancreatic head or duodenal involvement: gastrectomy combined with pancreaticoduodenectomy (GPD) and neoadjuvant chemotherapy followed by surgery (NCS). Methods: A retrospective analysis of patient data from January 2012 to January 2022 was conducted to evaluate the outcomes of these two treatment strategies. Results: The study included 284 patients, comprising 78 in the GPD group and 206 in the NCS group. In the NCS group, 119 patients required extended pancreaticoduodenectomy, a significantly smaller proportion compared to the GPD group (p < 0.001). The NCS group successfully avoided unnecessary extended pancreaticoduodenectomy. In contrast, 15 patients in the GPD group underwent surgery despite postoperative pathological confirmation of no pancreatic head or duodenal involvement (p < 0.001). The incidence of Clavien-Dindo grade ≥ IIIb complications was significantly greater in the GPD group than in the NCS group (10.3% vs. 3.3%, p = 0.034). Overall survival was significantly longer in the NCS group, with a median of 25 months compared to 20 months in the GPD group (p = 0.0005). Multivariate Cox regression analysis revealed that tumor diameter ≥7 cm and N3 stage were independent adverse prognostic factors. Conclusion: Neoadjuvant chemotherapy is recommended for patients with gastric cancer presenting clinical evidence of pancreatic head or duodenal involvement. This approach reduces unnecessary extended surgeries, lowers complication rates, and improves overall survival.

Gastrointestinal cancer (GIC) ranks among the most fatal malignancies globally and is characterized by a significant propensity for metastasis. While surgical intervention can effectively cure GIC in its early stages, a substantial number of cases are diagnosed at advanced stages, where the response to current therapeutic options is markedly diminished. Increasing evidence highlights the pivotal role of circadian rhythm, an intrinsic 24-hour cyclical system regulating biological activities to adapt to the alternations of day and night in the progression, metastasis, and development of chemoresistance in GIC. Recent studies have disclosed that the modulation of key circadian rhythm genes (such as BMAL1 and PER1) can suppress tumor advancement through multiple pathways. This review compiles the most recent research concerning the circadian rhythm and its influence on GIC progression. It elucidates the role of circadian genes in the initiation, metastasis, metabolism, inflammatory response, and therapeutic resistance in GIC, including both chemotherapy and targeted therapies. Furthermore, the review discusses the current implementation and future outlook of therapeutic strategies based on circadian modulation in the treatment of GIC.

BACKGROUND:A dysregulated immune system could become a vital trigger for gastric carcinogenesis. METHODS:Literature retrieval was performed based on PubMed, Web of Science, and Embase from inception to January 2025. Cohort studies investigating the risk ratio (RR) or incidence of gastric cancer among patients with autoimmune disorders were eligible. Relative risk was the primary endpoint [RR with 95% confidence interval (CI)], while incidence was the secondary endpoint. RESULTS:A total of 285 studies were included, containing 61 556 078 participants. Overall pooled RR was 1.158 (95% CI 1.098-1.222, P < 0.001). Patients with autoimmune gastritis (3.066, P < 0.001), systemic sclerosis (1.788, P = 0.010), type 1 diabetes (1.411, P < 0.001), sarcoidosis (1.388, P = 0.004), and psoriasis (1.194, P = 0.001) were strongly associated with a higher risk of gastric cancer. Meanwhile, patients with dermatomyositis (2.100, P = 0.034) and systemic lupus erythematosus (1.296, P = 0.038) were also associated with increased risk of gastric cancer, despite smaller effect sizes and higher P values. Subgroup analyses based on sex and geographical regions were also conducted. CONCLUSION:Autoimmune diseases were associated with increased gastric cancer risk, especially autoimmune gastritis, systemic sclerosis, type 1 diabetes, sarcoidosis, and psoriasis. Patients with dermatomyositis and systemic lupus erythematosus were potentially associated with an elevated risk of gastric cancer. Surprisingly, ulcerative colitis had a protective effect against gastric cancer, especially among East Asian countries. Regarding sex analysis, male and female patients were similarly susceptible to autoimmunity-induced gastric carcinogenesis. As for geographical differences, patients with autoimmune diseases from Nordic countries were most likely to have an increased risk of gastric cancer, while autoimmune diseases seemed to have protective effects against gastric cancer among Japanese patients, especially those with rheumatoid arthritis.

The objective of this study is to evaluate the efficacy of laparoscopic surgery combined with the rectal inversion and specimen extraction (RIES) technique for rectal cancer, focusing on both short-term and long-term outcomes. A retrospective comparative analysis was performed on 120 patients who underwent laparoscopic radical excision for rectal cancer from June 2017 to June 2021. Patients were categorized into two groups: Group RIES ([Formula: see text]), which received the novel RIES technique, and Group AIES ([Formula: see text]), which underwent the conventional abdominal incision for specimen extraction. Short-term outcomes, such as postoperative pelvic sepsis, temporary ileus, anastomotic leakage, and anastomotic stricture, were meticulously recorded. Long-term efficacy was evaluated through the 3-year overall survival (OS), disease-free survival (DFS), and local recurrence rate (LRR). The RIES group demonstrated a 3-year OS, DFS, and LRR of 86.2%, 77.6%, and 8.6%, respectively, with a low incidence of short-term complications. Comparatively, the AIES group showed a 3-year OS, DFS, and LRR of 83.9%, 74.2%, and 19.4%, respectively, with slightly higher rates of postoperative complications. Statistical analysis using the Student’s t-test, the chi-square ([Formula: see text]) test revealed no significant differences in the primary outcomes between the two groups, and suggested the noninferiority of the RIES technique. The study suggests that the RIES technique is a safe, feasible, and potentially functional and oncological superior approach to rectal cancer treatment, without compromising clinical efficacy. Further research is warranted to validate these findings in a larger, multicenter, and randomized controlled trial.

Peripheral nerve injury often causes significant function loss. Autologous nerve grafting as a gold-standard repair strategy for treating such an injury is limited by donor nerve supply. Tissue-engineered nerve guidance conduits (TENGCs) as a promising alternative for autografting are challenged by large nerve gaps. Herein, we fabricate a glutaraldehyde-cross-linked sericin nerve guidance conduit (GSC) incorporated with clobetasol, a glucocorticoid receptor agonist, for repairing a 10 mm long sciatic nerve gap in a rat model. The GSC exhibits biocompatibility and regeneration-favorable physicochemical properties. GSC's degradation products promote the secretion of neurotrophic factors in Schwann cells. By repurposing clobetasol for peripheral nerve regeneration, our work uncovers clobetasol's previously unknown functions in promoting Schwann cell proliferation and upregulating the expression of myelin-related genes. Importantly, the implantation of this clobetasol-loaded GSC in vivo leads to successful regeneration of the transected sciatic nerve. Strikingly, the regeneration outcome is functionally comparable to that of autologous nerve grafting (evidenced by three parameters). Specifically, the static sciatic index (SSI), relative reaction time (RRT) and nerve conduction velocity (NCV) in Clobetasol/GSC group are -74.55, 1.30, and 46.4 mm/s at Week 12, respectively, while these parameters are -64.53, 1.23, and 49.8 mm/s in Autograft group. Thus, this work represents the first report unveiling clobetasol's potential in peripheral nerve regeneration, reveals the feasibility of applying a sericin conduit for repairing a large nerve defect, and demonstrates the effectiveness of the clobetasol-loaded-GSC based strategy in transected nerves' regeneration.

BACKGROUND:Dysregulation of immune system could be a vital stimulant of colorectal cancer development. We aimed to provide the most comprehensive meta-analysis on this topic. METHODS:Observational cohort studies reporting incidence or risk ratio of colorectal cancer among patients with autoimmune disorders as exposures were eligible. Relative risk was the primary endpoint and adjusted risk ratio were effect sizes. Incident cases per 100 000 person-years at risk were used for incidence analysis as secondary endpoint. RESULTS:523 studies were included, containing 91 265 886 participants. Overall pooled risk ratio was 1.244 ( p < 0.001). The results were consistent irrespective of sub-localization (colon: 1.308, p < 0.001; rectum: 1.173, p < 0.001), sex (male: 1.229, p < 0.001; female: 1.209, p < 0.001) and country (Nordic: 1.301, p < 0.001; Western: 1.213, p < 0.001; East Asian: 1.213, p < 0.001). Specifically, primary sclerosing cholangitis, idiopathic inflammatory myopathies, inflammatory bowel disease, autoimmune hepatitis, ANCA-associated vasculitis, sarcoidosis, scleroderma, type 1 diabetes, psoriasis, membranous nephropathy, hidradenitis suppurativa and idiopathic thrombocytopenic purpura were associated with higherrisk of colorectal cancer. Interestingly, several autoimmune diseases might help to lower colorectal cancer risk, especially rheumatoidarthritis. CONCLUSIONS:Patients with autoimmune diseases were associated with higher risk of colorectal cancer under generally or specific settings. Unlike ourgastric and small bowel cancer pooled results, this risk-increasing impact on colorectal cancer was consistent across Nordic, Western and East Asian countries. Both digestive organ-specific or systemic autoimmune diseases could significantly increase risk of colorectal cancer. However, several autoimmune diseases might act as protective factors against colorectal cancer, especially rheumatoid arthritis, while not on gastric or small bowel carcinogenesis.

Correction for ‘pH-Triggered nanoreactors as oxidative stress amplifiers for combating multidrug-resistant biofilms’ by Lei Huang et al., Chem. Commun., 2021, 57, 4662–4665, https://doi.org/10.1039/D1CC00247C.

Gastric cancer (GC) is one of the most common and deadliest cancers worldwide. Lipid homeostasis is essential for tumour development because lipid metabolism is one of the most important metabolic reprogramming pathways within tumours. Elucidating the mechanism of lipid homeostasis in GC might significantly improve treatment strategies and patient prognosis. GSE62254 was applied to construct a lipid homeostasis-related gene signature score (HGSscore) by multiple bioinformatic algorithms including weighted gene coexpression network analysis (WGCNA) and LASSO-Cox regression. A nomogram based on HGSscore and relevant clinical characteristics was constructed to predict the survival of patients with GC. TIMER and xCell were used to evaluate immune and stromal cell infiltration in the tumour microenvironment. Correlations between lipid homeostasis-related genes and chemotherapeutic efficacy were analysed in GSCAlite. RT‒qPCR and cell viability assays were applied to verify the findings in this study. HGSscore was constructed based on eighteen lipid homeostasis-related genes that were selected by WGCNA and LASSO-Cox regression. HGSscore was strongly associated with advanced TNM stage and showed satisfactory value in predicting GC prognosis in three independent cohorts. Furthermore, we found that HGSscore was associated with the tumour mutation burden (TMB) and immune/stromal cell infiltration, which are related to GC prognosis, indicating that lipid homeostasis impacts the formation of the tumour microenvironment (TME). With respect to the GSCAlite platform, PLOD2 and TGFB2 were shown to be positively related to chemotherapeutic resistance, while SLC10A7 was a favourable factor for chemotherapy efficacy. Cell viability assays showed that disrupted lipid homeostasis could attenuate GC cell viability. Moreover, RT‒qPCR revealed that lipid homeostasis could influence expression of specific genes. We identified a lipid homeostasis-related gene signature that correlated with survival, clinical characteristics, the TME, and chemotherapeutic efficacy in GC patients. This research provides a new perspective for improving prognosis and guiding individualized chemotherapy for patients with GC.

Colorectal cancer (CRC) is a major cause of cancer mortality and a serious health problem worldwide. Mononuclear phagocytes are the main immune cells in the tumor microenvironment of CRC with remarkable plasticity, and current studies show that macrophages are closely related to tumor progression, invasion and dissemination. To understand the immunological function of mononuclear phagocytes comprehensively and deeply, we use single-cell RNA sequencing and classify mononuclear phagocytes in CRC into 6 different subsets, and characterize the heterogeneity of each subset. We find that tissue inhibitor of metalloproteinases (TIMPs) involved in the differentiation of proinflammatory and anti-inflammatory mononuclear phagocytes. Trajectory of circulating monocytes differentiation into tumor-associated macrophages (TAMs) and the dynamic changes at levels of transcription factor (TF) regulons during differentiation were revealed. We also find that C5 subset, characterized by activation of lipid metabolism, is in the terminal state of differentiation, and that the abundance of C5 subset is negatively correlated with CRC patients' prognosis. Our findings advance the understanding of circulating monocytes' differentiation into macrophages, identify a new subset associated with CRC prognosis, and reveal a set of TF regulons regulating mononuclear phagocytes differentiation, which are expected to be potential therapeutic targets for reversing immunosuppressive tumor microenvironment.

Background: Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. Objectives: To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Design: Meta-analysis. Data sources and methods: Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle–Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Results: Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality ( n = 31). Regarding resectable cases ( n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32–1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer ( n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23–2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27). Conclusion: As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations. Trial registration: PROSPERO (CRD42020168051).

BACKGROUND:This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. METHODS:Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. RESULTS:Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. CONCLUSIONS:Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.